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Pharmacology and behavioral pharmacology of the mesocortical dopamine system
Progress in Neurobiology 63 (2001) 241 – 320 www.elsevier.com/locate/pneurobio
Pharmacology and behavioral pharmacology of the mesocortical dopamine system T.M. Tzschentke * Gru¨nenthal GmbH, Research and De6elopment, Department of Pharmacology, Postfach 500444, 52088 Aachen, Germany Received 3 April 2000
Abstract The prefrontal cortex (PFC) has long been known to be involved in the mediation of complex behavioral responses. Considerable research efforts are directed towards refining the knowledge about the function of this brain area and the role it plays in cognitive performance and behavioral output. In the first part, this review provides, from a pharmacological perspective, an overview of anatomical, electrophysiological and neurochemical aspects of the function of the PFC, with an emphasis on the mesocortical dopamine system. Anatomy of the mesocortical system, basic physiological and pharmacological properties of neurotransmission within the PFC, and interactions between dopamine and glutamate as well as other transmitters within the mesocorticolimbic circuit are included. The coverage of these data is largely restricted to what is relevant for the second part of the review which focuses on behavioral studies that have examined the role of the PFC in a variety of phenomena, behaviors and paradigms. These include reward and addiction, locomotor activity and sensitization, learning, cognition, and schizophrenia. Although the focus of this review is on the mesocortical dopamine system, given the intricate interactions of dopamine with other transmitter systems within the PFC and the importance of the PFC as a source of glutamate in subcortical areas, these aspects are also covered in some detail where appropriate. Naturally, a topic as complex as this cannot be covered comprehensively in its entirety. Therefore this review is largely limited to data derived from studies using rats, and it is also specifically restricted to data concerning the medial PFC (mPFC). Since in several fields of research the findings concerning the function or role of the mPFC are relatively inconsistent, the question is addressed whether these inconsistencies might, at least in part, be related to the anatomical and functional heterogeneity of this brain area. © 2001 Elsevier Science Ltd. All rights reserved.
Contents 1. Introduction, aims and scope of the paper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. Pharmacology of the mesocortical dopamine system . . . . . . . . . . . . . . . . . . . 2.1. Anatomy of the mesocortical system . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. The dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Dopamine receptor distribution and localization . . . . . . . . . . . . . . . 2.1.3. The glutamatergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Other transmitter systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.1. The GABAergic system. . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.2. The noradrenergic system . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.3. Endogenous opioids. . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Basic physiological and pharmacological properties of neurotransmission within mPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Rates of activity of mesocortical dopaminergic neurons . . . . . . . . . . . 2.2.2. Responsivity to stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Tel.: +49-241-5692816; fax: + 49-241-5692852. E-mail address: [email protected] (T.M. Tzschentke). 0301-0082/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0301-0082(0 1)00033-2
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2.2.3. Responsivity to drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.1. Dopaminergic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.2. Glutamatergic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.3. Neuroleptics and antidepressants . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Role of the NA transporter for the reuptake of DA. . . . . . . . . . . . . . . . . 2.2.5. Transmitter co-localization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Interactions between dopamine and glutamate, and other transmitters, within the mesocorticolimbic circuit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Dopamine–glutamate–GABA interactions in the prefrontal cortex . . . . . . . . 2.3.1.1. Dopaminergic regulation of prefrontal pyramidal cells and interneurons 2.3.1.2. Glutamatergic regulation of prefrontal dopaminergic afferents . . . . . . 2.3.2. Dopamine–glutamate–GABA – acetylcholine interactions in the VTA . . . . . . . 2.3.2.1. Glutamatergic regulation of VTA dopamine neurons . . . . . . . . . . . 2.3.2.2. Cholinergic regulation of VTA dopamine neurons . . . . . . . . . . . . . 2.3.2.3. The role of VTA GABAergic neurons . . . . . . . . . . . . . . . . . . . . 2.3.3. Dopamine–glutamate–GABA interactions in the NAS . . . . . . . . . . . . . . . 2.3.3.1. Glutamatergic regulation of accumbal spiny neurons. . . . . . . . . . . . 2.3.3.2. Glutamatergic regulation of accumbal dopaminergic afferents . . . . . . 2.3.3.3. Dopaminergic regulation of accumbal glutamatergic afferents . . . . . . 2.3.4. The ‘inverse’ relationship between cortical and subcortical dopamine . . . . . . .
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4. Functional heterogeneity of the mPFC as a possible cause for inconsistent data? . . . . . . .
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Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Behavioral pharmacology of the mesocortical dopamine system. . . . . . . . . . . . . . . . . 3.1. Reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Conditioned place preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.1. Intracranial self-administration . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.2. Lesion effects on intravenous self-administration . . . . . . . . . . . . . . 3.1.3. Self-stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Addiction and craving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Motor behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Effects of intra-mPFC drug injections . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Effects of mPFC lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.1. 6-OHDA lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.2. Excitotoxic lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Behavioral sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Alterations in DA release during repeated drug administration . . . . . . . . . . 3.3.2. Lesion effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Possible differential role of the mPFC in cocaine- versus amphetamine-induced sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Schizophrenia and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Dopamine and glutamate hypotheses. . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Prepulse inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Latent inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. The relationship between dopaminergic tone and cognitive performance — the gating of information flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nomenclature 5-HT 6-OHDA Ach AMPA CCK
5-hydroxytryptamine 6-hydroxydopamine acetylcholine a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid cholecystokinin
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CPP DA DAT DOPAC EPSP FR GABA GAD67 HVA ICSS IPSP LI MD MFB mPFC NA NAS NMDA PCP PD PFC PPI PPTg SNc THC TTX VTA
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conditioned place preference dopamine dopamine transporter dihydroxyphenylacetic acid excitatory postsynaptic potential fixed ratio g-amino-butyric acid glutamic acid decarboxylase homovanillic acid intracranial self-stimulation inhibitory postsynaptic potential latent inhibition mediodorsal medial forebrain bundle medial prefrontal cortex noradrenaline nucleus accumbens septi N-methyl-D-aspartate phencyclidine Parkinson’s disease prefrontal cortex prepulse inhibition pedunculopontine tegmental nucleus Substantia nigra pars compacta D9-tetra-hydro-cannabinol tetrodotoxin ventral tegmental area
1. Introduction, aims and scope of the paper For a long time, the frontal poles of the cerebral cortex have received considerable attention in both neurology and experimental neurobiology. This region of the brain is generally termed prefrontal cortex (PFC) and it is thought that this region is primarily involved in ‘higher order cognitive functions’. Unfortunately, such functions are not always readily accessible in experimental animals. Nevertheless, a large number of paradigms and tests have been developed that can be used to examine the function of this region in rats, primates and other species. The major aim of this review is to provide a broad overview of what is known about the functional anatomy and pharmacology of the PFC and of work that has examined the functions of the PFC using behavioral pharmacological methods. The present review will focus primarily on rat studies. There is considerable debate about cross-species homologies of different frontal cortical areas, and discussion of this issue and the comprehensive consideration of data from other species would be beyond the scope of this review. Dopaminergic innervation of the PFC shows considerable cross-species differences, in particular there are substantial differences between rodents and primates with respect to the anatomical distribution of dopamine (DA) input but also with respect to
the expression of different DA receptor subtypes (Berger et al., 1991). Therefore, whenever possible and unless stated otherwise, the great majority of the data reviewed in this paper is derived from rat studies. Nevertheless, data from selected primate studies will be cited when this seems appropriate and where it helps to illustrate certain examples in cases where rat data is too limited to allow for general statements. Yet, the aim of this review is not to systematically compare and discuss rat and primate data. There exists a considerable number of topical as well as comprehensive reviews concerning the PFC, and I will refer to these reviews where appropriate, especially in cases where reference is made to early studies, or in cases where topics are touched which are of relevance for the present context but where it would be beyond the scope and the space limits of this review to cover the literature in detail. Furthermore, generally the focus of this review is on the coverage of data collected over the last two decades. Earlier studies are also included where necessary and meaningful, but much of this literature is covered by referring to appropriate review articles. A particular emphasis is put on the description of the anatomical and functional characteristics of the mesoprefrontocortical dopaminergic projection to the extent to which they are different from those of the mesoaccumbal/nigrostriatal dopaminergic projection. There-
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fore, it will be necessary to also cover the features of the latter projections in some detail. However, in contrast to the description of the mesocortical system the description of the mesolimbic system will not be comprehensive but will rather be limited to some selected, representative studies. The discussion of transmitter systems will largely be restricted to DA, glutamate, and GABA which does not mean to imply that other transmitter systems such as noradrenaline (NA), acetylcholine (Ach), serotonin (5-HT) and a number of peptide transmitters and neuromodulators such as the endogenous opioids, substance P, neurotensin, cholecystokinin (CCK) and others do not play an important role in PFC function. Nevertheless, it would be beyond the scope of this review to include all neurochemical aspects concerning the PFC, and in particular the numerous and complex interactions of the other transmitter systems with each other and with the dopaminergic, glutamatergic and GABAergic systems. For example, one transmitter system that is covered only superficially in this review is the serotonergic system, to the extent that prefrontal serotonergic mechanisms are thought to be involved in the action of atypical neuroleptic drugs. Serotonin undoubtedly plays an important role in the function of the PFC, but it would be beyond the scope of this paper to cover this large and complex literature in detail. Also, no attempt is made in this review to cover each and every aspect of the multitude of functions of the PFC. For example, areas that are not covered in this paper include the role of the PFC in autonomic regulatory processes, in emotionality and in social behavior. A very important point is that, whenever possible, the discussion in this review is restricted to the medial prefrontal cortex (mPFC). Other frontal cortical areas which are also considered to be part of the PFC such as the sulcal prefrontal cortex are deliberately not included in this review. Unfortunately, in many studies the anatomical specificity of experimental manipulations of the PFC is not entirely clear. Especially in many early studies lesions or local drug injections often affected large, ill-defined areas of the frontal cortex, i.e. various frontal cortical areas other than the mPFC. Whenever possible, the discussion in the present review is centered on studies that clearly focussed on the mPFC, particularly in the rat. The first main part of this review will give an overview of the pharmacology of the mesocortical dopamine system, including a summary of the anatomical organization of the dopaminergic system in relation to other transmitter systems, a summary of the basic physiological and neurochemical features of the mesocorticolimbic system, and of the functional relevance of the interactions of different transmitter systems within the mesocorticolimbic system. The second major part of the review will then address the functions of the mesocortical dopamine system as assessed with behavioral pharmacological
methods in experimental animals. This overview will cover the role of the mPFC in reward and addiction, motor behavior and sensitization, and schizophrenia, learning and cognition. Before concluding the review, a brief section will examine the possibility that the often inconsistent findings concerning the functional role of the mPFC may be due to the anatomical and functional heterogeneity of this brain region. 2. Pharmacology of the mesocortical dopamine system
2.1. Anatomy of the mesocortical system 2.1.1. The dopaminergic system Dopaminergic projections to the mPFC arise predominantly in the VTA (and to a small extent in the medial SNc) and innervate predominantly the infralimbic and prelimbic subareas, while the dopaminergic innervation of the anterior cingulate subarea is less prominent (Thierry et al., 1973; Fuxe et al., 1974; Ho¨kfelt et al., 1974; Beckstead, 1976; Berger et al., 1976; Simon et al., 1976, 1979a; Carter and Fibiger, 1977; Tassin et al., 1977, 1978a; Bjo¨rklund et al., 1978; Lindvall et al., 1978; Moore and Bloom, 1978; Beckstead et al., 1979; Haglund et al., 1979; Albanese and Bentivoglio, 1982; Swanson, 1982; Albanese and Minciacchi, 1983; Bjo¨rklund and Lindvall, 1984; Serrano et al., 1986; Oades and Halliday, 1987; Reader and Grondin, 1987; van Eden et al., 1987; Garris et al., 1993; Carr et al., 1999; Hedou et al., 1999). DA innervation of the mPFC shows a laminar distribution, with the deep layers (V, VI) receiving a denser dopaminergic input than the more superficial layers (Emson and Koob, 1978; Descarries et al., 1987; van Eden et al., 1987; Berger et al., 1988, 1991; Ciliax et al., 1995). This is consistent with the preferential occurrence of D1 and D2 receptors in these layers (Klemm et al., 1979; Dawson et al., 1985, 1986a,b; Dubois et al., 1986; Savasta et al., 1986; Charuchinda et al., 1987; Richfield et al., 1989; Mansour et al., 1990, 1991; Fremeau et al., 1991; Mengod et al., 1991; Huang et al., 1992; Vincent et al., 1993, 1995; Gaspar et al., 1995). Cortical pyramidal cells appear to be the primary targets of dopaminergic afferents to the mPFC (van Eden et al., 1987; Se´gue´la et al., 1988; Goldman-Rakic et al., 1989; Verney et al., 1990) although D1 and D2 receptors are also located on cells other than pyramidal cells in the mPFC (presumably GABAergic interneurons) (Vincent et al., 1993), and DA terminals also make contact with non-pyramidal, GABAergic cells (Verney et al., 1990; Benes et al., 1993; Sesack et al., 1995a,b). In fact, Vincent et al. (1995) have suggested that while D2 receptors are expressed in both pyramidal and nonpyramidal cells, D1 receptors may be expressed predominantly in nonpyramidal cells. With respect to the dopaminergic input onto pyramidal cells, it has been shown that dopaminergic boutons form symmetric (i.e. presumably inhibitory) synapses
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on dendritic spines of pyramidal cells. Asymmetric (i.e. presumably excitatory) synapses, probably originating from thalamo–cortical or cortico – cortical inputs, are often found in close apposition to the dopaminergic synapse on the same dendritic spine, while direct axo– axonic synapses are not observed (Goldman-Rakic et al., 1989; Smiley et al., 1992; Smiley and Goldman-Rakic, 1993; DeFelipe and Farinas, 1992). This ‘triad’ arrangement would be well suited to subserve the ‘gating’ function of DA on information flow mediated by glutamatergic neurotransmission (see section 3.4.4). From this ‘circuit perspective’ it is also interesting to note that DA terminals in the mPFC make direct contact with pyramidal cells that project to the NAS (Carr et al., 1999). Thus, the VTA can monosynaptically influence glutamatergic transmission in the NAS which may in turn presynaptically regulate DA transmission in the mPFC (see section 2.3). Different lines of anatomical, physiological and pharmacological (see section 2.1.2) evidence suggest that mesocortical and mesoaccumbal dopaminergic projections consist of two distinct populations of DA neurons. The cell bodies of these two neuronal populations are at least in part separated into distinguishable anatomical domains at the level of the VTA. Cells located in the nucleus paranigralis of the VTA predominantly project to subcortical sites, whereas cells located in the nucleus parabrachialis pigmentosus predominantly project to cortical sites, including the medial prefrontal cortex (Berger et al., 1976; Lindvall et al., 1978; Palkovits et al., 1979; Simon et al., 1979a; Deniau et al., 1980; Fallon, 1981; Slopsema et al., 1982; Swanson, 1982; Albanese and Minciacchi, 1983). Furthermore, VTA efferents to the mPFC and the NAS show only a relatively small degree of collateralization to other terminal regions such as striatum, septum, and entorhinal cortex (Lindvall et al., 1974, 1977; Fallon, 1981; Fallon and Loughlin, 1982; Swanson, 1982; Loughlin and Fallon, 1984; Sobel and Corbett, 1984). A fact emphasized by Swanson (1982) that has often been overlooked or neglected in functional – anatomical considerations of the transmitter interactions within the mesocorticolimbic circuit is that the VTA contains a considerable number of non-dopaminergic cells that project largely to the same terminal regions as the dopaminergic cells. For example, only 30% of the VTA-prefrontal projection is dopaminergic, while 85% of the VTA–NAS projection contains DA. Thus, in particular when considering the influence of the VTA on the mPFC these non-dopaminergic neurons may play a very important role, yet the current discussion in the literature centers almost exclusively on the dopaminergic part of this projection. There is good evidence that the non-dopaminergic part of the projection from the VTA to the mPFC is inhibitory and contains GABA as its transmitter (Thierry et al., 1980; Albanese
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and Bentivoglio, 1982; Swanson, 1982; Ferron et al., 1984; Gillham et al., 1990; Steffensen et al., 1998). This GABAergic projection may be important when considering the effects of VTA stimulation on mPFC cells (see section 2.3.2). As mentioned above, the VTA–NAS projection appears to be largely dopaminergic. Nevertheless, there is evidence that the non-dopaminergic part (15%, according to Swanson, 1982) of the projection from the VTA to the NAS/striatum is also GABAergic and appears to terminate predominantly on and modulates the activity of cholinergic interneurons which in turn input to medium spiny neurons (Pickel et al., 1988; Pickel and Chan, 1990; Rada et al., 1993; van Bockstaele and Pickel, 1995). Although cholinergic interneurons in the NAS/striatum are few in numbers, they can exert potent modulatory effects on the spiny GABAergic projection neurons. Thus, the relatively small GABAergic input from the VTA could nevertheless make an important contribution to the overall activity of striatal output. To make the picture even more complicated, GABA may also be co-localized with DA in some midbrain neurons projecting to the NAS/striatum (Kosaka et al., 1987).
2.1.2. Dopamine receptor distribution and localization DA receptors of the D1-type as well as of the D2type are present in the mPFC although their distribution shows only partial overlap (Scatton and Dubois, 1985; Dawson et al., 1986a,b; Bouthenet et al., 1987; Nisoli et al., 1988; Goldman-Rakic et al., 1990) and the density of D2 receptors appears to be considerably lower than that of D1 receptors (Liskowski and Potter, 1985; Martres et al., 1985; Boyson et al., 1986; Camus et al., 1986; Charuchinda et al., 1987; MeadorWoodruff and Mansour, 1991; Gaspar et al., 1995). This is consistent with the finding that the expression of D2 receptors is largely restricted to corticostriatal and corticocortical neurons in layer V while D1 receptors are found in layers II, V, and VI, and in corticostriatal, corticocortical but also in corticothalamic neurons (Goldman-Rakic et al., 1990; Vincent et al., 1993; Gaspar et al., 1995; Deutch et al., 1996; Lu et al., 1997b). The majority of D1 and D2 receptors within the mPFC appears to be located on pyramidal cells, but there is evidence that both receptor subtypes are also located on GABAergic interneurons (Al-Tikriti et al., 1992; Vincent et al., 1993, 1995; Smiley et al., 1994; Deutch et al., 1996; Grobin and Deutch, 1998) and on the terminals of afferents from the VTA (Fadda et al., 1984; see Gaspar et al., 1995). This receptor population may comprise the release-regulating autoreceptors discussed in section 2.2.1. There appears to be a good correlation between the overall cortical distribution of D1 and D2 receptor binding sites and the expression of the respective mRNA for these receptors (Choi et al., 1995), suggesting that the large majority of the receptors are
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located on cell bodies and dendrites of cells intrinsic to the mPFC and not on presynaptic axon terminals of mPFC afferents. Sesack and Bunney (1989) presented evidence that the D2-type receptor mediating the inhibitory effects of DA in the mPFC has pharmacological properties different from other D2 receptor populations. Initially, it was suggested that the receptors in question might actually be of the D3 or the D4 subtype (Sokoloff et al., 1980), but subsequently only very low levels of mRNA for D3 (Sokoloff et al., 1990; Bouthenet et al., 1991), D4 (van Tol et al., 1991) as well as D5 (Sunahara et al., 1991; Laurier et al., 1994) receptors have been found in the rat. On the other hand, using autoradiographic and, in particular, immunocytochemical methods, high levels of the D4 receptor subtype were found in the frontal cortex of rats (Ariano et al., 1997; Defagot et al., 1997; Tarazi et al., 1997). Interestingly, data from humans and non-human primates suggest that here the D1 and D4 receptor subtypes are the most abundant of all DA receptors expressed in frontal cortical areas. In fact, it appears that the prefrontal cortex is the only brain area with appreciable levels of D4 receptors in the primate brain, including humans (Corte´s et al., 1989; MeadorWoodruff et al., 1989, 1996; Lidow et al., 1991, 1998; Matsumoto et al., 1996). These D4 receptors may be at least in part located on GABAergic interneurons rather than on pyramidal cells (Mrzijak et al., 1996). The specificity of D4 receptor location in frontal cortical areas is also supported by the finding that peripheral administration of a D4 receptor antagonist induces c-fos expression only in the prefrontal cortex within the forebrain (Merchant et al., 1996; Feldpausch et al., 1998). The relative restriction of D4 receptors to the prefrontal cortex has raised hopes that specific ligands for these receptors may be effective in the treatment of mental diseases such as schizophrenia which are thought to involve prefrontal dysfunction (see section 3.4), without having prominent motor or other side effects. Unfortunately, the first selective ligands for this receptor entering clinical trials have proven to be ineffective in the treatment of schizophrenia (Kramer et al., 1997).
2.1.3. The glutamatergic system The main transmitter of the efferent mPFC projections is thought to be glutamate (Spencer, 1976; Divac et al., 1977; Kim et al., 1977; McGeer et al., 1977; Carter, 1980, 1982; Godukhin et al., 1980; Fonnum et al., 1981; Walaas, 1981; Druce et al., 1982; Hassler et al., 1982; Fonnum, 1984; Koller et al., 1984; Kornhuber et al., 1984; Ottersen and Storm-Mathissen, 1984; Christie et al., 1985a,b, 1987; Sandberg et al., 1985; Girault et al., 1986a; Young and Bradford, 1986; Butcher and Hamberger, 1987; Palmer et al., 1989; DeFelipe and Farinas, 1992; Ray et al., 1992).
The mPFC is not only the origin of a number of prominent glutamatergic projections but also receives considerable excitatory, glutamatergic input from cortical and subcortical sources. The most prominent of the cortical afferents originates from the contralateral mPFC, and the most prominent of the subcortical afferents originates from the mediodorsal thalamus (Leonard, 1969; Krettek and Price, 1977; Divac et al., 1978; Groenewegen, 1988; Groenewegen et al., 1990; Conde´ et al., 1990, 1995; Barbas et al., 1991; Gigg et al., 1992; Ray and Price, 1992; Kuroda et al., 1993; Pirot et al., 1994, 1995; Gioanni et al., 1999). In fact, the prefrontal cortex has been defined in the literature as the cortical region receiving afferents from the mediodorsal thalamus (Rose and Woolsey, 1948; Divac et al., 1993; Kuroda et al., 1998; see Uylings and van Eden, 1990; Groenewegen et al., 1997, for further discussion). Other prominent glutamatergic inputs to the mPFC have also been described, e.g. from the hippocampus (Jay et al., 1992; Conde´ et al., 1995; Carr and Sesack, 1996) and the amygdala (Groenewegen et al., 1990; Kita and Kitai, 1990; Bacon et al., 1996). A direct interaction between DA and glutamate in the mPFC is supported by the observation that dopaminergic and glutamatergic terminals are localized in close apposition to each other on the same postsynaptic pyramidal cell in the mPFC (Goldman-Rakic et al., 1989; Verney et al., 1990; Smiley and Goldman-Rakic, 1993; Pickel and Sesack, 1995; Carr and Sesack, 1996; Kuroda et al., 1995, 1996) such that presynaptic as well as postsynaptic interactions could be possible (see section 2.3.1 for further discussion). The prefrontal cortex is a cortical region particularly rich in NMDA and AMPA receptors (Monaghan et al., 1984; Monaghan and Cotman, 1985; Sakurai et al., 1991; Martin et al., 1993; Petralia et al., 1994a,b), and most if not all pyramidal cells appear to express both types of receptors (Pirot et al., 1995). Glutamatergic input to the mPFC is a crucial determinant of pyramidal cell activity. As mentioned above, the MD thalamus provides an important source of cortical glutamate. In addition, mPFC efferents form collaterals that feed back onto pyramidal cells. Interestingly, these two glutamatergic inputs can be differentiated on the basis of the type of glutamate receptor that mediates their effects and of how these inputs are modulated by DA. As Pirot et al. (1995) have shown, thalamic input to pyramidal cells is almost entirely mediated by AMPA receptors while input from recurrent collaterals is largely mediated by NMDA receptors, but to a small degree also by AMPA receptors. The same group (Pirot et al., 1996) has also shown that the direct thalamic input is not affected by local DA application or concurrent stimulation of the VTA while the excitation generated by input from recurrent collaterals is inhibited by increased DA.
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An additional interesting anatomical and functional distinction between these two glutamate receptor types has been found by Zhang and Shi (1999). They reported that in a slice preparation dendritic focal glutamate application induced repetitive bursts in most cells tested. On the other hand, in the same cells, somatic focal glutamate application induced only regular spiking but no burst activity. The bursting induced by dendritic glutamate could be reduced by both the NMDA receptor antagonist CGP37849 and the AMPA receptor antagonist NBQX, suggesting that NMDA as well as AMPA receptors are involved in the generation of the burst activity. However, selective activation of dendritic AMPA receptors by AMPA produced only regular spiking while selective activation of dendritic NMDA receptors by NMDA largely mimicked the burst-inducing effects of glutamate. These data suggest that burst activity in layer V/VI mPFC pyramidal cells is induced only by glutamatergic input onto dendrites but not onto the cell body. They also suggest that both NMDA and AMPA receptors are activated during dendritic glutamate activation, but that the bursting effect is primarily mediated by NMDA receptors. An apparently common feature of most corticolimbic and basal ganglia structures is that reciprocal connections exist between them and that in addition many structures are interconnected directly or indirectly. For example, while the VTA sends dopaminergic projections to the mPFC and NAS, the mPFC sends glutamatergic projections to the VTA and also to the NAS (Powell and Leman, 1976; Beckstead, 1979; Phillipson, 1979; Carter, 1982; Koller et al., 1984; Phillipson and Griffiths, 1985; Christie et al., 1985a,b, 1987; Girault et al., 1986b; Sesack et al., 1989; Berendse et al., 1992; Sesack and Pickel, 1990, 1992; Smith et al., 1996; Gorelova and Yang, 1997; Carr et al., 1999). These projections have a clear topographical organization (Sesack et al., 1989; Berendse et al., 1992; Zeng and Stuesse, 1993). For example, the dorsal parts of the mPFC (anterior cingulate and dorsal prelimbic area) project preferentially to the striatum and also to the dorsal aspects of the NAS, while the ventral parts of the mPFC (ventral prelimbic and infralimbic area) project preferentially to the ventral aspects of the NAS (Sesack et al., 1989). Dopamine – glutamate interactions at the level of the NAS/striatum are suggested by the finding that dopaminergic efferents from the VTA and glutamatergic efferents from the mPFC terminate in close apposition to each other, often on the same spine of the postsynaptic cell in the NAS/striatum (Bouyer et al., 1984; Freund et al., 1984; Sesack and Pickel, 1992). Interestingly, mPFC projections to the VTA synapse on dopaminergic as well as on non-dopaminergic cells, and the latter contacts may even be more numerous than the former (Sesack and Pickel, 1992; Smith et al., 1996). On the other hand, efferents from the mPFC
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have also been shown to directly contact DA neurons in the VTA that project to the NAS (van Eden and Feenstra, 1997). The consideration of these findings may be very important when discussing the behavioral and neurochemical effects of mPFC manipulations. Finally, the NAS sends GABAergic projections to the VTA and/or substantia nigra pars reticulata which, in turn, via thalamic nuclei, project back to the mPFC (Nauta et al., 1978; Phillipson, 1979; Walaas and Fonnum, 1980; Groenewegen and Russchen, 1984; Groenewegen, 1988; Ray and Price, 1992; Deniau et al., 1994). Furthermore, a direct feedback loop between the mPFC and the MD thalamus has also been described, such that fibers from the MD thalamus synapse on pyramidal cells in the mPFC that project back to the MD thalamus (Kuroda et al., 1993). Thus, on a ‘systems’ level, the mPFC and adjacent regions of the frontal cortex are parts of various partly parallel and functionally segregated, partly interconnected basal ganglia–thalamocortical circuits. A detailed anatomical and functional consideration of these circuits is beyond the scope of this present paper, therefore the interested reader is referred to a number of comprehensive reports and reviews on this topic (Alexander et al., 1986, 1990; Groenewegen et al., 1990; Parent, 1990; Gerfen, 1992; Zahm and Brog, 1992; Joel and Weiner, 1994, 1997; Pennartz et al., 1994; Houk and Wise, 1995; Parent and Hazrati, 1995; Wright and Groenewegen, 1995, 1996; Montaron et al., 1996; Maurice et al., 1997, 1998a,b, 1999; Lavin and Grace, 1998; Smith et al., 1998; Groenewegen et al., 1999).
2.1.4. Other transmitter systems 2.1.4.1. The GABAergic system. A very important element in the mPFC are the GABAergic interneurons (Ottersen and Storm-Mathissen, 1984; Esclapez et al., 1987). The available data suggest a rather complex mutual interplay of synaptic modulation of GABAergic, dopaminergic and glutamatergic neurotransmission within the mPFC (see section 2.3.1 for a more detailed account of these regulatory interactions). The picture is further complicated by the fact that these GABAergic interneurons do not constitute a homogenous cell population but comprise different, morphologically and functionally distinct cell populations (Kawaguchi and Kubota, 1993, 1996; Kawaguchi, 1993, 1995; Deutch and Duman, 1996; Sesack et al., 1998b). Direct (presumably mutual) synaptic connections exist between pyramidal cells and interneurons (DeFelipe and Farinas, 1992), and interneurons have been shown to possess NMDA receptors, AMPA/kainate receptors, and DA receptors of the D1 as well as of the D2 receptor family (Huntley et al., 1994; Mrzijak et al., 1996; Muly et al., 1997). Thus, these interneurons are intricately involved in mPFC synaptic interactions.
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2.1.4.2. The noradrenergic system. The mPFC also receives a dense noradrenergic innervation originating from the locus coeruleus (Foote et al., 1983; Bjo¨rklund and Lindvall, 1986), and DA and NA have been shown to interact in a number of ways although there appears to be only a partial overlap between dopaminergic and noradrenergic terminals. DA terminals are found mainly in the deeper layers of the mPFC while NA terminals are found mainly in the more superficial layers of the mPFC (Bjo¨rklund and Lindvall, 1984; Moore and Card, 1984). The mPFC has a relatively high density of a2-receptors (Talley et al., 1996) which may primarily be located presynaptically to regulate the release of DA (Ueda et al., 1983) and NA (Dennis et al., 1987). Prominent functional pre- and postsynaptic interactions between DA and NA have been determined and will be discussed in subsequent sections. 2.1.4.3. Endogenous opioids. Another transmitter system to be considered in the context of neural transmission within the mPFC is the endogenous opioid system which may be of particular relevance for mechanisms of motivation and reward (see section 3.1). Relatively high levels of d-receptors and somewhat lower levels of mand k-opioid receptors as well as their corresponding mRNAs are expressed in the mPFC with a clear laminar distribution, although less is known about the distribution of these receptors at the cellular level (Mansour et al., 1987, 1988, 1994, 1995a; Ding et al., 1996). Delfs et al. (1994), Mansour et al. (1995b) found a mismatch of m-receptor binding sites such that relatively high levels of m-receptors were found in the anterior cingulate and other cortical areas in the absence of in situ hybridization staining for the corresponding mRNA. This may suggest that cortical m-receptors are primarily located presynaptically on terminals of afferent neurons, which would be consistent with the finding that m-agonists can presynaptically modulate release of NA in a cortical slice preparation (Chesselet, 1984). m-opioid agonists can clearly influence synaptic transmission (Heijna et al., 1990; Wood and Rao, 1991; Vezina et al., 1992) and cell firing (Tanaka and North, 1994; Giacchiono and Henriksen, 1996) in the mPFC, although this latter effect of systemically administered opioids may in large part be indirectly mediated by the action of the drugs in other brain areas rather than directly by the action on opiate receptors within the mPFC (Giacchiono and Henriksen, 1996). The findings concerning the consequences of mPFC manipulations for the behavioral effects of opiates are inconsistent (see sections below), therefore it is not clear to what extent opioid receptors within the mPFC contribute to the overall behavioral effects of systemically administered opiates.
2.2. Basic physiological and pharmacological properties of neurotransmission within the mPFC A number of striking as well as subtle particularities of the mesocortical DA projection as compared to subcortical DA projections have been described in the literature. Many of these particularities relate to the basic physiological, pharmacological and functional properties of mesocortical dopaminergic cells and the manner in which they release DA in the mPFC.
2.2.1. Rates of acti6ity of mesocortical dopaminergic neurons The DA innervation of the mPFC is less dense than that of the NAS/striatum in terms of absolute extracellular basal DA levels and tissue DA content (Kolb, 1984; Plantje et al., 1987; Garris et al., 1993; Ihalainen et al., 1999). It has been shown at the cell body level in the VTA and at the axon terminal level in the mPFC that mesocortical DA neurons express lower levels of DA reuptake transporter sites than mesoaccumbal DA neurons (Javitch et al., 1985; Mennicken et al., 1992; Shimada et al., 1992; Ciliax et al., 1995; Freed et al., 1995; Nirenberg et al., 1997a,b; Sesack et al., 1998a). Related to this may be the finding that DA can diffuse over a longer distance and is cleared less rapidly from the extracellular space in the mPFC as compared with NAS or striatum (Garris et al., 1993; Garris and Wightman, 1994; Cass and Gerhardt, 1995; Lee et al., 1996). Also, the ratio of extracellular DA to whole tissue DA is higher than in other forebrain structures, which may be related to the higher relative rates of turnover and release, and/or lower relative rates of reuptake of DA observed in the mPFC as compared to other DA terminal regions (Bannon et al., 1981; Anden et al., 1983a; Sharp et al., 1986a; Hoffmann et al., 1988; Maisonneuve et al., 1990; Garris et al., 1993; Garris and Wightman, 1994). The higher relative rates of release, in turn, may be due to the higher basal firing rates, including more burst activity, and the more efficient stimulation-release coupling of mesofrontal DA neurons (Bannon and Roth, 1983; Chiodo et al., 1984; White and Wang, 1984; Chiodo, 1988; Hoffmann et al., 1988) and also to the fact that these neurons do not possess DA synthesis-modulating and impulse-regulating autoreceptors (Bannon et al., 1980, 1981, 1982, 1983; Anden et al., 1983b; Chiodo et al., 1984; Galloway et al., 1986; Wolf et al., 1986; Wolf and Roth, 1987; Hoffmann et al., 1988), although there is good evidence that they do carry DA release-modulating autoreceptors (Shepard and German, 1984; Galloway et al., 1986; Talmaciu et al., 1986; Altar et al., 1987; Plantje et al., 1987; Wolf and Roth, 1987; Hoffmann et al., 1988; Cubeddu et al., 1990; Bean and Roth, 1991; Fedele et al., 1993). On the other hand, clear evidence exists that dopaminergic transmission in the NAS and
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striatum is under strong autoreceptor control at various levels (modulation of release, synthesis, impulse-flow) (Groves et al., 1975; Aghajanian and Bunney, 1977; Nowycky and Roth, 1978; Starke et al., 1978; Roth, 1979; Skirboll et al., 1979; Kamal et al., 1981; Bannon et al., 1982; Cubeddu and Hoffmann, 1982; Haubrich and Pflueger, 1982; Hoffmann and Cubeddu, 1982; Parker and Cubeddu, 1985; Hoffmann et al., 1986, 1988). Furthermore, mesocortical DA neurons appear to express higher levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA biosynthesis (Bayer and Pickel, 1990; Blanchard et al., 1994), which may be related to the absence of synthesis-regulating autoreceptors and the high rates of release of DA in the mPFC. Also, mesocortical DA neurons are distinguished from mesoaccumbal DA neurons at the cell body level in the VTA by more excitatory (glutamatergic) and less inhibitory (GABAergic) inputs (Bayer and Pickel, 1991), which might further add to the particular properties of mesocortical cells. Interestingly, Garris and Wightman (1994) found that electrical stimulation of the medial forebrain bundle at physiological frequencies (10 – 20 Hz) produced the same (absolute) maximum overflow of DA in the mPFC as in the NAS and striatum, despite the great differences in the densities of the DA terminal fields in these different areas. Based on DA tissue contents alone, one would have expected the extracellular concentration of DA in the mPFC to be 90-fold less than in the NAS or striatum. The authors concluded that the unusually high DA concentrations in the mPFC are the results of a very high rate of DA release and the absence of an appropriately effective reuptake system. While the NAS and striatum were said to be ‘uptake dominated’ (i.e. extracellular DA levels are determined not so much be the rates of release but rather by the rates of reuptake), the mPFC was considered to be ‘release dominated’ (i.e. extracellular levels of DA are determined by the rates of release and not by the rates of reuptake). Due to the particular relative rates of release and reuptake, DA is thought to have a considerably longer extracellular half-life in the mPFC than in the NAS and striatum and is therefore able to diffuse over longer distances, possibly also to extrasynaptic sites (see discussion in Garris and Wightman, 1994). Thus, in the mPFC the physiological and anatomical framework would allow for DA ‘volume transmission’ (Herkenham, 1987; Vizi and Labos, 1991; Zoli et al., 1999), a feature thought not to exist for DA in the NAS or striatum (Garris and Wightman, 1994). Although too little is known so far about possible functional implications of such a non-synaptic transmission, it is clear that it adds an additional level of complexity to the analysis of the functioning of the mPFC.
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2.2.2. Responsi6ity to stress The mesocortical DA projection is particularly responsive to stress at low intensities that are not sufficient to activate the mesoaccumbal and mesostriatal projections to a comparable degree (Thierry et al., 1976a; Fadda et al., 1978; Lavielle et al., 1978; Tassin et al., 1980; Herman et al., 1982; Deutch et al., 1985, 1991a; Tam and Roth, 1985; Carlson et al., 1987b; Roth et al., 1988; Abercrombie et al., 1989; Mantz et al., 1989; Deutch and Roth, 1990; Pei et al., 1990; Bradberry et al., 1991; Kaneyuki et al., 1991; Cenci et al., 1992; Imperato et al., 1990c, 1991, 1992b; Sorg, 1992; Deutch, 1993; Kurata et al., 1993; Morrow et al., 1993; Sorg and Kalivas, 1993a,b; Inoue et al., 1994; Jedema and Moghaddam, 1994; Rasmusson et al., 1994; Feenstra and Botterblom, 1996; Nakahara and Nakamura, 1999), although it should be mentioned that a recent report shows that the mesoamygdaloid dopaminergic projection appears to be even more responsive to stress (Inglis and Moghaddam, 1999). A similar preferential activation of glutamatergic (Gilad et al., 1990; Moghaddam, 1993; Bagley and Moghaddam, 1997) and serotonergic (Kawahara et al., 1993; Yoshioka et al., 1995) transmission in the mPFC by stress has also been reported. Furthermore, noradrenaline release in the mPFC is also very sensitive to stress-activation (Hata et al., 1990; Rossetti et al., 1990; Gresch et al., 1994; Dalley and Stanford, 1995; Feenstra et al., 1995c, 1999; Finlay et al., 1995; Taber and Fibiger, 1997b). This, in turn, may also be relevant for the stress effects on DA given the potent mutual interactions between both transmitter systems. The mPFC is not only particularly sensitive to the effects of acute stress but also to the effects of chronic stress. Thus, compared to controls, rats preexposed to chronic cold, isolation stress or variable unpredictable stress showed a large increase in extracellular levels of both DA and NA and of DA metabolism in the mPFC but not in the NAS or striatum in response to an acute stressor (Blanc et al., 1980; Gresch et al., 1994; Cuadra et al., 1999). In addition to stress, DA in the mPFC is also increased by other salient environmental stimuli. For example, feeding can increase the release of DA (Hernandez and Hoebel, 1990; Feenstra and Botterblom, 1996), and as for stress, this effects appears to be more pronounced in the mPFC than in subcortical areas (Hernandez and Hoebel, 1988; Bassareo and Di Chiara, 1997). DA release in the mPFC is also particularly sensitive to exposure to novelty (Feenstra et al., 1995a; Feenstra and Botterblom, 1996; Rebec et al., 1997; see also Yee, 2000). 2.2.3. Responsi6ity to drugs 2.2.3.1. Dopaminergic drugs. DA uptake inhibitors generally have smaller effects on extracellular DA levels in
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the mPFC relative to the NAS or striatum (Hadfield and Nugent, 1983; Moghaddam and Bunney, 1989; Izenwasser et al., 1990; Elsworth et al., 1993; Wheeler et al., 1993; Cass and Gerhardt, 1995). Similarly, the stimulatory effects of D2 receptor antagonists on extracellular DA levels have been shown to be much more pronounced in the striatum as compared to the mPFC (Moghaddam and Bunney, 1990; Yamamoto et al., 1994). Consistent with the low levels of D2 (auto-) receptors in the mPFC (see section 2.1.2), it was found that systemic haloperidol induced a moderate increase in extracellular levels of DA in the striatum while having no significant effect in the mPFC. Also, while systemic amphetamine induced an increase in DA in both regions, this effect was by far greater in the striatum. On the other hand, co-administration of both drugs produced a considerably potentiated effect on extracellular DA levels in both structures, i.e. although haloperidol alone had virtually no effect on DA levels in the mPFC it significantly potentiated the DA-increasing effects of amphetamine (Pehek, 1999). This haloperidol-induced potentiation of amphetamine-stimulated DA efflux in striatum and mPFC appears to be mediated by different DA receptor populations, since the interactive effect of haloperidol and amphetamine in the striatum was blocked by the D1/D2 receptor agonist apomorphine, while this drug had no effect in the mPFC. On the other hand, the haloperidol–amphetamine interaction in the mPFC was significantly attenuated by the D2/D3 agonist quinpirole (Pehek, 1999). From these results it was concluded that there are D2-like (release-inhibiting) autoreceptors in the mPFC that are normally ‘silent’ under basal conditions and only come into play when extracellular levels of DA are considerably elevated. In other words, basal levels of DA are not autoreceptor-regulated in the mPFC while stimulated DA release is modulated via autoreceptor feedback (see also Wolf and Roth, 1987). The nature of this proposed type of autoreceptor is not clear, but the lack of effect of apomorphine, the effectiveness of quinpirole, and the findings of Gobert and collegues suggest that the effects might be mediated by D3 receptors (Gobert et al., 1995, 1996). The findings of Pehek (1999) are in good agreement with a number of other studies that have also shown a strong synergistic effect on extracellular DA levels in the striatum of a DA uptake inhibitor and a D2 receptor antagonist (Sharp et al., 1986b; Westerink et al., 1987; Gudelsky et al., 1992), and the results of Watanabe et al. (1989) show that both the effects of the uptake blocker and of the receptor antagonist are mediated locally within the striatum. In line with the diminished effects of DA uptake inhibitors on extracellular DA levels in the mPFC it has been found that the mPFC shows a smaller K+-evoked DA release relative to the striatum (Moghaddam et al.,
1990). In contrast to this, the anxiogenic beta-carboline FG 7142 produces a DA release in the mPFC but not in the striatum and NAS (Tam and Roth, 1985; Roth et al., 1988; Moghaddam et al., 1990; Bassareo et al., 1996) which may be related to the stress-inducing effects of this drug. A further functional distinction is that the mesocortical DA neurons are less sensitive to destruction by 6-OHDA than mesolimbic DA neurons, a fact that might be related to the higher relative density of noradrenergic innervation of the mPFC as compared to the NAS (Foote et al., 1983; Bjo¨rklund and Lindvall, 1986; Herve´ et al., 1986; Audet et al., 1988) since a high noradrenergic tonus may have neuroprotective effects in forebrain areas (Martel et al., 1999).
2.2.3.2. Glutamatergic drugs. A further difference between the cortical and subcortical dopaminergic systems lies in the way glutamate tonically and phasically regulates the basal release of DA in both regions at the cell body level in the VTA. Thus, basal NAS DA release is affected (i.e. reduced) to a much lesser degree than basal mPFC DA release by the injection of the NMDA receptor antagonist AP5 into the VTA (Karreman et al., 1996; Takahata and Moghaddam, 1998). Likewise, blockade of AMPA/kainate receptors in the VTA had no effect on DA release in the NAS (Chergui et al., 1993; Karreman et al., 1996; Westerink et al., 1996; Schilstro¨m et al., 1998) while it produced a clear reduction in basal extracellular DA levels in the mPFC (Takahata and Moghaddam, 1998). Furthermore, it has been demonstrated several times that systemic application of a non-competitive NMDA receptor antagonist (e.g. MK-801, PCP) or local administration of noncompetitive or competitive NMDA receptor antagonists is much more effective in increasing DA transmission in the mPFC than in the NAS or striatum (Bowers and Hoffman, 1984; Deutch et al., 1987; Rao et al., 1990a,b; Liljequist et al., 1991; Svensson et al., 1991; Bubser et al., 1992; Wedzony et al., 1993a,b; Nishijima et al., 1994, 1996; Verma and Moghaddam, 1996; Umino et al., 1998). These findings suggest that the basal activity of the two dopaminergic systems are under differential control of glutamate via NMDA receptors on the one hand and via AMPA/kainate receptors on the other hand. Interestingly, there is evidence to suggest that the DA-releasing effects of non-competitive NMDA receptor antagonists may be dependent upon their affinity for the PCP-binding site within the receptor-associated ion channel and the voltage-dependency of the binding. MK-801 and PCP, drugs that potently increase DA transmission in the mPFC, have a high affinity for the PCP-binding site and low voltage-dependency. On the other hand, memantine, a drug that has only moderate affinity for the PCP-binding site but strong voltage-dependency
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(see Parsons et al., 1993, 1996), has only very moderate effects on dopaminergic activity in the mPFC, both after acute and repeated (14 days) administration of a high dose (20 mg/kg) (Hesselink et al., 1999; see also Bubser et al., 1992). Furthermore, the finding of Nishijima et al. (1996) that TTX infusion into the mPFC completely blocked the increase in extracellular DA levels induced by systemic PCP suggests that the increase in mPFC DA produced by NMDA receptor antagonists depends upon an increase in impulse flow in the mesocortical DA projection. Rather different results were reported by Mathe´ et al. (1999). These authors found that basal levels of DA in mPFC and NAS and the MK-801 -induced increase in extracellular levels of DA in the NAS were both significantly reduced by intra-VTA infusion of tetrodotoxin (TTX). However, the MK-801 -induced increase in extracellular levels of DA in the mPFC was not significantly affected (Mathe´ et al., 1999). These findings suggest that while basal levels of DA in NAS and mPFC as well as the MK-801 -induced increase in NAS DA levels are dependent on impulse activity of the DA neurons, MK-801 increases extracellular levels of DA in the mPFC independently of impulse activity in DA neurons. This mechanism might involve local GABAergic interneurons (Yonezawa et al., 1998) and/or glutamate signalling via non-NMDA receptors (Moghaddam et al., 1997). These latter findings correspond well with electrophysiological data showing that MK-801 increases burst firing in neurons which presumably project to the NAS but reduces burst firing in neurons which presumably project to the mPFC (Murase et al., 1993b). When, despite the decrease in burst firing of DA neurons, a clear increase in extracellular levels of DA in the mPFC is observed after systemic MK-801 administration, this strongly suggests that MK-801 produces its effects independently of impulse flow. This implies that the regulation by glutamate (and possibly GABA) at the cell body level as well as at the nerve terminal level is quite different for mesocortical and mesoaccumbal DA neurons. This is in agreement with the findings of Kalivas et al. (1989) concerning the dichotomy at the level of the VTA for glutamate-induced stimulation of DA release/ metabolism in the two terminal regions. While glutamate injected into the VTA increased post-mortem levels of DA metabolites in both NAS and mPFC, injection of NMDA into the VTA selectively increased DA metabolism in the mPFC, and injection of kainate into the VTA selectively increased DA metabolism in the NAS. Also, coadministration of the competitive NMDA receptor antagonist CPP together with glutamate into the VTA selectively blocked the increase in DA metabolism in the mPFC but had no effects on DA metabolism in the NAS. Finally, intra-VTA injection of CPP also blocked the increase in DA metabolism in-
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duced by mild footshock stress (Kalivas et al., 1989). These data suggest that at the level of the VTA, glutamate-induced activation of dopaminergic activity in the mesolimbic and mesocortical system is mediated by different glutamate receptors. The stimulatory effect on mesocortical DA transmission appears to be mediated predominantly via NMDA receptors while the stimulatory effects on mesoaccumbal DA transmission are mediated via kainate (and possibly AMPA) receptors. It is intriguing to speculate if or how the impulse-dependent and impulse-independent effects on cortical DA release relate to the observed differences in the way mPFC DA release is regulated by NMDA receptors on the one hand and AMPA receptors on the other hand (Jedema and Moghaddam, 1996; Takahata and Moghaddam, 1998). Blockade of NMDA or AMPA receptors in the VTA as well as blockade of AMPA receptors in the mPFC reduced DA release in the mPFC (Takahata and Moghaddam, 1998). On the other hand, systemic competitive and non-competitive blockade of NMDA receptors, but not AMPA receptors, enhanced DA release or turnover in the mPFC (Hata et al., 1990; Wedzony et al., 1993b; Hondo et al., 1994; Nishijima et al., 1994; Bubser et al., 1995; Verma and Moghaddam, 1996). Conversely, activation of NMDA receptors reduced basal DA release when a relatively low dose of NMDA (0.1 mM) was infused into the mPFC (although a high dose of NMDA (1 mM) produced an increase in extracellular DA) (Feenstra et al., 1995b; Jedema and Moghaddam, 1996). Finally, infusion of AMPA or kainate into the mPFC produced a clear increase in extracellular levels of DA (Jedema and Moghaddam, 1996). This suggests that glutamate exerts a tonic excitatory influence on the dopaminergic system via AMPA and NMDA receptors in the VTA and via AMPA receptors in the mPFC and a tonic inhibitory influence via NMDA receptors in the mPFC (Takahata and Moghaddam, 1998). The inhibitory effects of NMDA receptor stimulation on prefrontal cortical DA release may be due to a preferential localization of NMDA receptors on GABAergic interneurons within the mPFC the activity of which has been shown to have an inhibitory influence on DA release (Santiago et al., 1993). That dopaminergic activity may be regulated differentially by AMPA receptors in the mPFC and in the NAS is also suggested by the findings of Bubser et al. (1995) who found that coadministration of the AMPA receptor antagonist GYKI 52466 blocked the increase in DA metabolism induced by the NMDA receptor antagonist MK-801 only in the NAS but not in the mPFC. The picture of glutamatergic regulation of DA release in the mPFC is further complicated by the fact that there may be differences between glutamatergic regulation of basal versus stimulus-evoked DA release. As in the case of regulation of basal DA release,
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blockade of AMPA and NMDA receptors in the VTA (Kalivas et al., 1989; Enrico et al., 1998) and of AMPA receptors in the mPFC reduced or blocked the DA release in response to handling stress. However, blockade of NMDA receptors in the mPFC, although increasing basal DA levels, had no effect on handling and tail pinch stress-induced DA release (Jedema and Moghaddam, 1994; Takahata and Moghaddam, 1998). Thus, prefrontal cortical NMDA receptors appear to be involved in the regulation of basal but not of stressevoked DA release. It remains to be determined, however, if this holds also true for the increase in DA release induced by other, non-stressful stimuli (Imperato et al., 1992b; Feenstra and Botterblom, 1996; Taber and Fibiger, 1997a,b).
2.2.3.3. Neuroleptics and antidepressants. The mesocortical DA projection was also found to be particularly responsive (in comparison to subcortical sites) to antidepressant drugs (Tanda et al., 1994; Gobert et al., 1997; Millan et al., 1997), the anticonvulsant mood stabilizers valproate and carbamazepine (Ichikawa and Meltzer, 1999), and ‘atypical’ neuroleptic drugs (Hand et al., 1987; Moghaddam and Bunney, 1990; Robertson and Fibiger, 1992; Moghaddam, 1994; Nomikos et al., 1994; Pehek and Yamamoto, 1994; Yamamoto and Cooperman, 1994; Schmidt and Fadayel, 1995; Deutch and Duman, 1996; Volonte´ et al., 1997; Li et al., 1998; Kuroki et al., 1999). In particular the preferential increase in prefrontal DA metabolism induced by ‘atypical’ neuroleptics has elicited a great deal of interest. It has been hypothesized that this effect may be related to the affinity of these drugs for the 5-HT2A receptor rather than for the D2 receptor (Leysen et al., 1993; Aghajanian and Marek, 1999) and that this preferential activation of prefrontal DA transmission may account for the improvement of negative symptoms of schizophrenia, which are thought to be related to prefrontal cortical dopaminergic hypofunction (Davis et al., 1991; Deutch et al., 1991b; Weinberger and Lipska, 1995; Tollefson and Sanger, 1997), brought about by these drugs. The suggestion that this effect of ‘atypical’ neuroleptic drugs may be due to their antagonistic effects at 5-HT2A receptors is consistent with the finding that local infusion of the 5-HT2A/c agonist DOI increases mPFC levels of GABA (Abi-Saab et al., 1998) and, in turn, clozapine clearly decreases extracellular levels of GABA in the mPFC (while haloperidol has only weak effects on mPFC GABA) (Bourdelais and Deutch, 1994). 5-HT2A receptors in the mPFC are located on interneurons as well as on pyramidal cells (Jakab and Goldman-Rakic, 1997; Willins et al., 1997), and interneurons are the target of serotonergic axon terminals (Smiley and Goldman-Rakic, 1996). Given these findings, it seems feasible that ‘atypical’ neuroleptics exert their effects on extracellular DA levels in the
mPFC by blocking serotonin-mediated GABA release at 5-HT2A receptors, thus relieving DA terminals from GABAergic inhibition (Santiago et al., 1993). An interesting anatomical finding of potential functional significance has recently been reported by Garzo´n et al. (1999).The authors showed that cholinergic axon terminals in the VTA make asymmetric (i.e. presumably excitatory) synapses only with cells that express no or only low levels of the plasmalemmal DA transporter (DAT). Since mesocortical DA neurons express lower levels of DAT than mesolimbic DA neurons (see section 2.2.1), this finding suggests that cholinergic input to the VTA modulates exclusively, or at least preferentially, the mesocortical system. Unfortunately, in the study of Garzo´n et al. (1999) the origin of the cholinergic afferents to the VTA were not determined, but there is evidence that the cholinergic innervation of the VTA originates in the pedunculopontine tegmental nucleus (PPTg) (Gould et al., 1989; Blaha et al., 1996; Yeomans and Baptista, 1997).
2.2.4. Role of the NA transporter for the reuptake of DA The NA transporter contributes importantly to the removal of DA from the extracellular space in the mPFC. DA has an even greater affinity for the NA transporter than NA itself, and the NA transporter has a denser and more widespread distribution than the DA transporter within the mPFC (Raiteri et al., 1977; Carboni et al., 1990; Izenwasser et al., 1990; Elsworth et al., 1993; Gehlert et al., 1993; Pozzi et al., 1994; Tanda et al., 1994; Bannon et al., 1995; Gresch et al., 1995a; Lee et al., 1996). The importance of NA transporter blockade by cocaine and amphetamine for the increase in extracellular levels of DA in the mPFC induced by these drugs has also been pointed out (Tanda et al., 1997). The relative importance of noradrenergic transmission (as compared to dopaminergic transmission) in the mPFC (as compared to NAS or striatum) is also suggested by the fact that the ratio of NA to DA concentration in the mPFC is 10 (Slopsema et al., 1982) while it is only 0.01 in the striatum (Palkovits, 1979). However, it is somewhat difficult to evaluate the importance of these mechanisms for the elimination of DA since the NA innervation of the mPFC is not homogeneous and appears to be relatively sparse in the deep layers of the prelimbic mPFC (Berger et al., 1976; Lindvall and Bjo¨rklund, 1984; Moore and Card, 1984; Cass and Gerhardt, 1995), that part of the mPFC which receives the densest DA innervation. Nevertheless, elevation of extracellular levels of NA by local application of desipramine significantly increased extracellular levels of DA and strongly potentiated stress-induced increases in extracellular DA levels in the mPFC (Tassin, 1992; Gresch et al., 1995b). These effects may be due either to a direct stimulatory action of NA on
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presynaptic DA release or to the fact that increased levels of extracellular NA will increase competition between DA and NA for available NA transporters, thus decreasing the relative proportion of DA taken up by the NA transporter (Raiteri et al., 1977; Carboni et al., 1990; Pozzi et al., 1994). Conversely, the release of NA appears to be regulated via D2 receptors within the mPFC (Rossetti et al., 1989). These potent interactions between DA and NA are a recurrent issue in 6-OHDA lesion studies of the mPFC, and a differential degree of NA depletion in addition to DA depletion induced by 6-OHDA injection may be an important factor when considering the variable results obtained in studies examining 6-OHDA lesion effects on behavior and neurotransmission within the mPFC and in subcortical areas (see Bunney and Aghajanian, 1976; Carter and Pycock, 1978, 1980; Tassin et al., 1979, 1986; see sections 3.2.2.1 and 4 for more details and references).
2.2.5. Transmitter co-localization A further distinguishing feature of mesocortical DA neurons lies in the nature of the cotransmitters which are co-localized with DA in these neurons. There is data to suggest that co-localization of neurotensin is a common feature of all mesocortical DA neurons while other dopaminergic projections co-localize neurotensin to varying but small degrees (Ho¨kfelt et al., 1984; Kalivas and Miller, 1984; Seroogy et al., 1987, 1988; Studler et al., 1988; Bean et al., 1989a). Since in the mPFC neurotensin is released under the same conditions of activity as DA (Bean et al., 1989b; Hertel et al., 1996) and since neurotensin has been shown to have potent physiological and behavioral effects in the mPFC (Rompre´ et al., 1998) it may well be the case that the release of neurotensin during activity of mesocortical neurons significantly contributes to the observed effects of this activity. DA neurons projecting to the NAS preferentially co-localize cholecystokinin (CCK). Thus, different physiological or behavioral effects of activity of mesocortical and mesolimbic projections might also be due to different effects of the co-localized transmitters in the respective target regions rather than or in addition to different effects of DA alone. 2.3. Interactions between dopamine and glutamate, and other transmitters, within the mesocorticolimbic circuit 2.3.1. Dopamine–glutamate – GABA interactions in the prefrontal cortex 2.3.1.1. Dopaminergic regulation of prefrontal pyramidal cells and interneurons. Although the action of DA on glutamatergic cells in the mPFC has received the most attention, considerable evidence also suggests that dopaminergic, serotonergic, glutamatergic and noradren-
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ergic inputs, along with intrinsic GABAergic transmission, make up a complex network of interactions among the different transmitter systems, most of which can influence each other mutually. It is beyond the scope of this review to give a detailed account of all the interactions of the different transmitter systems within the mPFC that have been described to date, but a number of exemplary studies will be summarized to demonstrate the complexity of the nature of interactions, with a focus on DA/glutamate/GABA interactions. The focus of interest in our present context are the effects of DA on the activity of the glutamatergic efferents of the mPFC (pyramidal cells). Many studies have addressed this issue, and the picture that emerges from these studies is complex. On the electrophysiological level, one cannot simply state that DA in the mPFC has this or that effect on pyramidal neurons, but the effects of DA depend on a whole number of factors that are important in determining the effects of DA. The most general picture that emerges from a number of studies is that DA or DA agonists applied directly into the mPFC or stimulation of DA release by means of chemical or electrical activation of the VTA generally inhibits the activity of pyramidal cells in the mPFC (Bunney and Aghajanian, 1976; Mora et al., 1976; Reader et al., 1979; Bernardi et al., 1982; Ferron et al., 1984; Rolls et al., 1984; Sawaguchi and Matsumura, 1985; Thierry et al., 1986; Gratton et al., 1987; Jahkel et al., 1987; Peterson et al., 1987, 1990; Mantz et al., 1988; Thierry et al., 1986, 1988; Sesack and Bunney, 1989; Parfitt et al., 1990; Qiao et al., 1990; Yang and Mogenson, 1990; Godbout et al., 1991; Karreman and Moghaddam, 1996; Gulledge and Jaffe, 1998; Gobbi and Janiri, 1999). Whether DA inhibition of pyramidal cells is a direct or an indirect effect is not entirely clear but evidence exists that the inhibitory effect of DA on pyramidal cells may involve both an excitation of GABAergic interneurons by DA, which would in turn inhibit the pyramidal cells (Mercuri et al., 1985; PenitSoria et al., 1987; Re´taux et al., 1991a; Pirot et al., 1992; Grobin and Deutch, 1998) and a direct inhibitory action of DA on pyramidal cells (Geijo-Barrientos and Pastore, 1995; Gulledge and Jaffe, 1998). However, the effects of DA on the postsynaptic cell can depend on the type of cell and on the type of DA receptor activated. While the effects of DA on GABAergic cells appear to be mediated primarily by the D2 receptor (Re´taux et al., 1991a; Grobin and Deutch, 1998), it is not clear yet which receptor type mediates the effects of DA on pyramidal cells, and both receptor types (D1 and D2) have been implicated (Sesack and Bunney, 1988; Parfitt et al., 1990; Godbout et al., 1991; Pirot et al., 1992; Law-Tho et al., 1994; Gulledge and Jaffe, 1998). It should be noted here, however, there is some controversy about the exact nature of the D2 receptor
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type thought to be involved in these mechanisms since the effect of endogenous DA is not blocked by haloperidol and is also not mimicked by the D2 agonist quinpirole (Sesack and Bunney, 1988; Godbout et al., 1991). This suggests that an additional, pharmacologically not yet well characterized D2-type receptor may exist in the mPFC. The picture is further complicated by the fact that several different, morphologically, neurochemically and physiologically distinct sub-populations of pyramidal cells and interneurons exist (Grace and Llinas, 1984; Kawaguchi and Kubota, 1993, 1996; Kawaguchi, 1993, 1995; Yang et al., 1996a,b; Gabbott and Bacon, 1995, 1996a,b, 1997; Gabbott et al., 1997) which may also respond differentially to dopaminergic input (Deutch and Duman, 1996). In addition, the effects of DA also depend on whether the postsynaptic cell is in a rested or in an active (depolarized) state (Hernandez-Lopez et al., 1997; Stern et al., 1997; Ce´peda et al., 1998), on whether proximal or distal dendrites of the postsynaptic cell are activated (Yang and Seamans, 1996) and on whether other (glutamatergic, GABAergic, noradrenergic, serotonergic, cholinergic) inputs to the postsynaptic cell are also active (Yang and Mogenson, 1990; Beauregard and Ferron, 1991; Ce´peda et al., 1992; Surmeier and Kitai, 1993, 1997; Law-Tho et al., 1995; see Yang et al., 1999, for a recent comprehensive review of electrophysiological actions of DA in the mPFC). In this context, it is also interesting to note that the inhibitory effects of DA were mainly observed in in vivo preparations (see references above), while in vitro preparations have generally shown a depolarizing effect of DA on mPFC neurons (Penit-Soria et al., 1987; Yano et al., 1989, 1991; Law-Tho et al., 1994; GeijoBarrientos and Pastore, 1995; Shi et al., 1997; Ceci et al., 1999). Finally, pyramidal cell responses to NMDA receptor stimulation depends on the concentration of DA present at the synapse. Zheng et al. (1999) found that low concentrations of DA enhanced current responses to NMDA application while high concentrations reduced these responses. Interestingly, these differential effects were specifically related to D1 and D2 receptors in that the activating effect of DA was mediated by the D1 receptor and the inhibitory effect of DA was mediated by the D2 receptor. As Yang and Seamans (1996), p.1932) put it: ‘‘… the action of DA on pyramidal PFC neurons is neither ‘excitatory’ nor ‘inhibitory’ but depends on the foci, timing, and strength of synaptic inputs, as well as on the membrane potential range at which the PFC neuron is operating.’’ As in the striatum (Braun and Chase, 1986; Carlson et al., 1987a; Walters et al., 1987; White, 1987), there seems to exist a synergism between D1 and D2 receptor-mediated events such that activation of the one receptor type can enhance the responses to activation of the other receptor type, or that activation of one recep-
tor type even is necessary for the expression of responses to stimulation of the other receptor type (Sesack and Bunney, 1988; Re´taux et al., 1991b).
2.3.1.2. Glutamatergic regulation of prefrontal dopaminergic afferents. It was mentioned above that stress increases the release of DA and glutamate preferentially in the mPFC compared to other basal ganglia structures. However, it is not quite clear to date how these two phenomena relate to each other. Generally, stimulation of dopaminergic activity (release, metabolism) in the mPFC after local and peripheral administration of non-competitive as well as competitive NMDA receptor antagonists has been reported (Hata et al., 1990; Tanii et al., 1990; Wedzony et al., 1993b; Hondo et al., 1994; Nishijima et al., 1994; Kashiwa et al., 1995; Wheeler et al., 1995; Jedema and Moghaddam, 1996; Yonezawa et al., 1998). However, ionotropic glutamate receptors have not yet been convincingly shown to be present on dopaminergic terminals in the mPFC (Fink et al., 1992; Petralia and Wenthold, 1992; Petralia et al., 1994a,b; DeBiasi et al., 1996), and it may be that glutamate influences dopaminergic transmission in the mPFC predominantly via ionotropic receptors located on GABAergic terminals and/or dendrites (Nishijima et al., 1994; Feenstra et al., 1995b; DeBiasi et al., 1996). In this respect, the situation appears to be different in the NAS, since there metabotropic rather than ionotropic glutamate receptors regulate basal and stimulated DA release (Taber and Fibiger, 1995; Feenstra et al., 1998) although some evidence for the existence of NMDA receptors on dopaminergic terminals in the NAS also exists (French et al., 1985). The findings for the effects of NMDA receptor agonists have been more inconsistent. Increases (Cheramy et al., 1986; Jhamandas and Marien, 1987; Jones et al., 1993; Feenstra et al., 1995b), decreases (Cheramy et al., 1986; Feenstra et al., 1995b) and no effects (Jedema and Moghaddam, 1996; Yonezawa et al., 1998) on dopaminergic activity of NMDA receptor agonists have been reported. The dose-dependent effects found by Feenstra et al. (1995b), Cheramy et al. (1986) suggest that these discrepant findings may be, at least in part, be explained by the use of different doses of the agonist. The findings of Jones et al. (1987, 1988, 1993), Feenstra et al., (1993) that electrical or chemical stimulation of excitatory afferents to the mPFC increases dopaminergic activity in the mPFC, however, suggests that physiologically released glutamate in the mPFC may indeed stimulate DA release at the terminal level. The effects of AMPA/kainate receptor blockade or stimulation on extracellular DA levels in the mPFC have not been studied yet to the same extent, but the available data suggest that DA release is stimulated by agonists of these receptors (Jones et al., 1993; Jedema and Moghaddam, 1996). Furthermore, blockade of
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AMPA (and possibly NMDA) receptors in the mPFC blocked the local stress-induced increase in DA release (Jedema and Moghaddam, 1994). The most straightforward explanation for these findings would be that activation of glutamate transmission in the mPFC by stress would — via presynaptically located AMPA or NMDA receptors — increase the release of DA within the mPFC. Nevertheless, alternative explanations also exist. For example, activation of glutamatergic transmission in the mPFC by stress or experimental manipulations could lead to a stronger activation of the glutamatergic projections from the mPFC to the VTA (directly or via the PPTg), which in turn could stimulate mesocortical DA neurons in the VTA to release more DA into the mPFC. A further possibility is that the increased release of glutamate in the mPFC induced by stress is not involved in the concurrent increase in DA release, neither directly nor indirectly. It could be that DA release is stimulated by activation of dopaminergic cells at the level of the VTA by excitatory input unrelated to the mPFC. Since the VTA also receives excitatory input from the amygdala, the hippocampus and the PPTg, glutamatergic input to the VTA from these sources could also lead to enhanced DA release in the mPFC (Deutch and Roth, 1990; Kalivas et al., 1989; Kalivas, 1993; Morrow et al., 1993). The effects of endogenous glutamate on extracellular levels of DA and its metabolites, and of GABA have been studied by Del Arco and Mora (1999). These authors found that increasing extracellular levels of glutamate in the mPFC by local infusion of the glutamate uptake inhibitor PDC increases GABA levels, does not affect DA levels and decreases levels of the DA metabolites DOPAC and HVA. The increase in extracellular GABA was blocked by the AMPA/kainate receptor antagonist DNQX but was not affected by the competitive NMDA receptor antagonist CPP. Conversely, the PDC-induced decrease in extracellular DA metabolites was blocked by CPP but was not affected by DNQX. These results suggest that endogenous glutamate increases GABAergic activity in the mPFC primarily via AMPA/kainate receptors while it decreases DA metabolism primarily by acting on NMDA receptors. This also implies that the reduction of dopaminergic activity in the mPFC by glutamate is not secondary to an increase in inhibitory GABAergic transmission. These data are not entirely consistent with the results of Yonezawa et al. (1998) who found that NMDA receptor antagonists decreased extracellular levels of GABA in the mPFC while, however, NMDA failed to increase extracellular GABA. Taken together, these results would imply that basal extracellular levels of GABA are (positively) regulated via NMDA receptors while glutamate-induced stimulation of GABA release is mediated via AMPA/kainate receptors.
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Finally, GABA is also positively modulated by DA (presumably predominantly via the D2 receptor) (Grobin and Deutch, 1998) and in turn, GABAergic transmission modulates mPFC DA release (presumably via both GABA-A and GABA-B receptors) (Santiago et al., 1993).
2.3.2. Dopamine–glutamate–GABA–acetylcholine interactions in the VTA 2.3.2.1. Glutamatergic regulation of VTA dopamine neurons. Using ligand binding, in situ hybridization and immunohistochemical methods, relatively high levels of GABA-A and GABA-B receptors, and of NMDA and non-NMDA glutamate receptors have been shown to be present in midbrain dopaminergic neurons (Albin et al., 1992; Petralia and Wenthold, 1992; Martin et al., 1993; Sato et al., 1993; Standaert et al., 1993, 1994; Laurie and Seeburg, 1994; Petralia et al., 1994a,b; Lu et al., 1999a,b). These receptors are likely to be the basis of the electrophysiological and neurochemical effects of locally or systemically applied glutamate and GABA agonists and antagonists. In a series of studies, Westerink and collegues (Santiago and Westerink, 1991, 1992; Westerink et al., 1992, 1996, 1998) carried out a pharmacological analysis of the regulation of the major dopaminergic projections (nigrostriatal, mesolimbic, and mesocortical) at the level of the VTA. These studies revealed similarities as well as differences between the different projections in their response to pharmacological manipulation in the VTA. With respect to GABAergic modulation it was found, for example, that while intra-VTA application of the GABA-A agonist muscimol reduced extracellular levels of DA in both the NAS and the mPFC it actually increased extracellular DA in the striatum. On the other hand, a comparable increase in DA was seen in all 3 terminal areas after intra-VTA administration of the GABA-A antagonist bicuculine. Intra-VTA infusion of the GABA-B antagonist baclofen moderately reduced extracellular levels of DA in the mPFC but strongly reduced DA in the NAS and striatum. With respect to glutamatergic modulation it was found that NMDA infusion into the VTA produced a pronounced but short-lasting increase in extracellular DA in the mPFC, but a weaker and more prolonged DA increase in the NAS and striatum. On the other hand, infusion of kainate into the VTA produced a moderate and transient increase in DA in the mPFC and NAS while it produced a small but delayed and long-lasting increase in DA in the striatum. These data suggest that different populations of dopaminergic neurons are under complex and differential control of GABAergic and glutamatergic (as well as dopaminergic and cholinergic; see references below) inputs.
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The effects of glutamate antagonists as well as agonists on DA cell activity can be quite different in in vitro versus in vivo preparations and also in anesthetized versus awake animals. The general picture that has emerged from numerous and partly controversial papers is that the results can be grouped into three broad categories according to the methods used. (1) Using the slice preparation, where naturally occurring bursts are absent (Grace and Bunney, 1983, 1984a,b; Sanghera et al., 1984; Grace and Onn, 1989) NMDA and AMPA/kainate receptor antagonists had no consistent effects of the electrophysiological activity of VTA cells (Wang and French, 1993a). On the other hand, glutamate, NMDA, AMPA and kainate all increased firing rate without inducing burst activity (Seutin et al., 1990; Wang and French, 1993a,b). The effect of NMDA was found to be biphasic in that low to intermediate doses of NMDA had clear stimulatory effects on the firing rate while high doses reduced firing rate, possibly due to depolarization inactivation. These alterations in firing rate closely correlated with DA release in the NAS when the VTA was perfused with the same doses of NMDA via a microdialysis probe (Wang et al., 1994). It should be mentioned that there is one report showing that bursting can be induced in the slice preparation by application of NMDA (but not kainate or quisqualate) (Johnson et al., 1992). However, this effect appears to be due to the particular procedures and methods employed in that study so that these results cannot necessarily be compared to the majority of the other slice studies (see references for details). Interestingly, Wang and French (1995) found, using intracellular recordings, that AMPA, kainate and NMDA (in this potency rank order) also depolarized non-DA neurons in the VTA. (2) Using direct local drug application onto DA cells (most commonly by microiontophoresis) in the anesthesized whole animal, no effects were found for MK-801 (Zhang et al., 1992) and only relatively weak, inhibitory effects were observed for PCP (Freeman and Bunney, 1984; French, 1986a), while the glutamate receptor antagonist kynurenic acid reduced spontaneous burst firing activity (Charle´ty et al., 1991). On the other hand, iontophoretic administration of the receptor agonists AMPA, kainate, glutamate and NMDA (in this potency rank order) produced an increase in cell firing and in burst activity in dopaminergic as well as nondopaminergic cells, at least in the substantia nigra (Zhang et al., 1994). As mentioned above, glutamate agonists increase firing rate but do not induce burst firing in VTA slice preparations. Based on the available data it is difficult to determine whether the induction of burst activity in this study is due to the fact that the experiments were done in whole animals, as opposed to the slice, or whether this observation represents a difference between VTA and substantia nigra cells. (3) Using systemic drug application in whole
animals, PCP increased average firing rate at low to intermediate doses and decreased firing rate at very high doses (Freeman and Bunney, 1984; Pawlowski et al., 1990; French et al., 1991; French, 1986a, 1992). MK-801 and TCP, but interestingly not the competitive NMDA receptor antagonists CGS 19755, NPC 12626 and CPP, also increased average firing rate and in some cases also burst activity (French et al., 1991, 1993; French, 1992; Zhang et al., 1992; Murase et al., 1993b). In fact, the ability of non-competitive NMDA receptor antagonists to increase firing in DA neurons is positively correlated to their channel-blocking potency (French and Ceci, 1990), and the stimulatory effect of low to moderate doses of PCP can be blocked or attenuated by coadministration of competitive NMDA receptor antagonists, suggesting that the stimulatory effect of PCP (at least at low to moderate doses) is largely due to its channel-blocking properties (‘use-dependency’) (French, 1992). Interestingly, Zhang et al. (1993) found that MK-801 reduced the firing rate of nondopaminergic VTA neurons. Based on this, it is tempting to speculate that the stimulatory effects of systemic NMDA receptor antagonists on DA cell firing are at least partly due to a indirect, disinhibitory mechanism at the level of the VTA, such that PCP, MK-801 and related drugs block the activity of GABAergic interneurons in the VTA, thus relieving DA neurons from GABAergic inhibition. This ‘local-loop’ mechanism is consistent with the finding that hemitransections that separate the forebrain from the midbrain attenuate but do not completely block the excitatory effects of systemic MK-801 on DA neurons (Zhang et al., 1992). It is also consistent with the above-mentioned demonstration that non-DA neurons in the VTA are depolarized by AMPA, kainate and NMDA (Wang and French, 1995). The effects of glutamatergic drugs on the firing pattern of dopaminergic cells in general and on the burst activity of these cells in particular are of great interest because of the relationship between cell firing pattern and DA release in the terminal regions. Most importantly, firing rate and DA release are non-linearly related in that burst activity is particularly effective in releasing DA at high rates (Gonon and Buda, 1985; Gonon, 1988; Chergui et al., 1994a). The marked lack of effect of competitive NMDA receptor antagonists on the electrophysiology despite their marked overall behavioral effects is a phenomenon that has not been explained satisfactorily to date, but it implies that blockade of the NMDA receptor-associated ion channel has other or additional ionic, and therefore in effect electrophysiological, consequences than blockade of the glutamate binding site. Taken together, these results suggest that glutamatergic afferents to the VTA are crucial for the generation of burst activity. This suggestion is supported by the
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observation that stimulation of structures that send glutamatergic projections to the VTA/SN also induces burst firing in midbrain DA neurons (PFC: Gariano and Groves, 1988; STN: Smith and Grace, 1992; Chergui et al., 1994b; PPTg: Di Loreto et al., 1992; Lokwan et al., 1999; see also Kitai et al., 1999). At the DA cell level in the VTA NMDA receptor antagonists reduce the activity of these cells but in the intact animal this inhibitory effect is overridden by the activation of potent excitatory inputs from other brain areas to the VTA and/or by local disinhibitory mechanisms that result in a net increase in DA cell activity and increased bursting. The fact that systemically administered MK801 does not block these excitatory inputs onto DA cells may be nicely explained by the finding of Mathe´ et al. (1998) who suggested that the stimulatory, glutamatergic effect of MK-801 is mediated via AMPA receptors at the level of the VTA, which would be unaffected by the systemically administered MK-801. The influence of the mPFC on dopaminergic neurotransmission is particularly obvious from studies in which the effects of activation or inactivation of the mPFC on the activity of DA neurons in the VTA were examined. Chemical or electrical stimulation of the mPFC increases the firing rate and changes the firing pattern of DA neurons in the VTA (Thierry et al., 1979; Gariano and Groves, 1988; Chergui et al., 1993, 1994b; Murase et al., 1993a). In fact, electrical stimulation of the mPFC at the appropriate parameters produces burst firing in DA neurons that is virtually indistinguishable from naturally occurring burst events (Overton et al., 1996; Overton and Clark, 1997; Tong et al., 1996a,b, 1998) and, as mentioned above, glutamatergic input to the VTA appears to be essential for the induction of bursts since spontaneous burst activity does not occur in slice preparations (Pinnock, 1983; Grace and Bunney, 1984a,b; Sanghera et al., 1984; Silva and Bunney, 1988; Grace and Onn, 1989; Seutin et al., 1990; Suaud-Chagny et al., 1992). On the other hand, temporary inactivation of the mPFC reduces firing rate and the occurrence of burst firing in DA neurons (Svensson and Tung, 1989; Murase et al., 1993a), and systemic and local administration of glutamate (in particular NMDA) receptor antagonists also reduces the occurrence of burst activity (Grenhoff et al., 1988; Charle´ty et al., 1991; Overton and Clark, 1992; Chergui et al., 1993). Furthermore, ibotenic acid lesions of the mPFC decrease the number of spontaneously active cells in the VTA (Shim et al., 1996; note, however, that in this study the mPFC lesions produced an increase in firing rate in SN dopaminergic cells, suggesting that mPFC input to different DA neuron populations in the midbrain does not have uniform effects on the activity of these populations). The increase in burst firing in VTA neurons as a result of mPFC stimulation probably directly accounts for the increase in DA release in the
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NAS observed during mPFC stimulation (Taber and Fibiger, 1993, 1995; Nissbrandt et al., 1994; Taber et al., 1995; You et al., 1998). This effect is mediated by the activation of NMDA — but not AMPA — receptors in the VTA (Overton and Clark, 1992; Chergui et al., 1993; Taber et al., 1995; Karreman and Moghaddam, 1996; Karreman et al., 1996; Tong et al., 1996a). It has been mentioned above that the effects of DA in the mPFC not only depend on the type of postsynaptic cell upon which it acts but also on the state (i.e. level of membrane de- or hyperpolarization due to the activity of other inputs) of that postsynaptic cell. The findings of Kiyatkin and Rebec (1998) suggest that the same may also be true for the effects of glutamate (and GABA) upon dopaminergic cells in the VTA. They found that presumed dopaminergic neurons responded with different degrees of monophasic excitation, biphasic excitation-inhibition, or weak monophasic inhibition to the same amount of iontophoretically applied glutamate current depending on their activity state prior to glutamate application or on the behavioral state of the animal (which in turn presumably influenced the activity state of the DA neurons). Thus, as it is too simplistic to state that DA ‘simply’ inhibits postsynaptic cells in the mPFC, it is also probably inappropriate to state that glutamate ‘simply’ excites postsynaptic cells in the VTA. Difficult to reconcile with the evidence reviewed above is the finding by Harden et al. (1998) that 6-OHDA lesions of the mPFC also decreased activity of DA neurons in the VTA (slower mean firing rate, decrease in relative burst activity, but no effect on the number of spontaneously active cells). This effect cannot be explained by the mechanisms outlined above according to which DA inhibits mPFC glutamatergic efferents to the VTA which stimulate DA neurons. It could, however, be easily explained if the predominant targets of mPFC glutamatergic input to the VTA were indeed GABAergic interneurons which inhibit DA neurons. An alternative explanation would involve the mPFC glutamatergic efferents to the NAS which stimulate GABAergic spiny neurons which in turn project to the VTA and inhibit DA neurons. Whichever mechanism turns out to be correct, neither of them can be reconciled with the explanations for effects of increased DA in the mPFC or electrical stimulation of the mPFC, both of which postulate a direct or indirect (i.e. longloop) excitatory influence of glutamatergic mPFC efferents on VTA DA neurons. Interestingly, very similar 6-OHDA lesions and experimental conditions like those of Harden et al. (1998), i.e. lesions that reduced the activity of dopaminergic neurons, did not have significant effects on basal extracellular levels of DA in the NAS but did augment stress-induced DA release in the NAS (King et al., 1997). This implies that compensa-
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tory mechanisms in the NAS were induced by mPFC DA depletion to maintain extracellular DA concentration at pre-lesion levels despite reduced DA cell activity. These mechanisms might include a decreased sensitivity of DA autoreceptors or a decreased activity of DA reuptake transporters in the NAS. These compensatory mechanisms might also explain the increased DA response to stress (see Harden et al., 1998 for further discussion). Based on anatomical and electrophysiological grounds it appears likely that the stimulatory effect of mPFC stimulation on DA cell activity (and probably also the influence of the mPFC under natural physiological conditions) is in large part not mediated by a direct glutamatergic input to VTA DA cells from the mPFC (although a direct effect may also be possible; see McCormick et al., 1985; Overton and Clark, 1997). Glutamatergic afferents of the VTA originating from the mPFC synapse predominantly on non-DA cells (Sesack and Pickel, 1992) and the latencies of the DA neuron response to mPFC stimulation are too long for a monosynaptic connection (Tong et al., 1996b, 1998). Thus, it seems more likely that the effects of mPFC stimulation on DA cell firing are mediated via a oligoor polysynaptic loop which possibly includes the PPTg, which receives cortical input (Moon-Edley and Graybiel, 1983), has a direct, excitatory projection to the VTA (Phillipson, 1979; Jackson and Crossman, 1983; Scarnati et al., 1986) the transmitters of which appear to be glutamate and acetylcholine (Scarnati et al., 1986; Clements and Grant, 1990; Futami et al., 1995; Takakusaki et al., 1996; Grofova and Zhou, 1998). The impact of prefrontal glutamatergic input to non-DA cells in the VTA on DA cell activity has been examined by Tong et al. (1998). From their data the authors concluded that the glutamatergic input to non-DA cells in the VTA is primarily monosynaptic and does not affect the immediate firing behavior or the properties of individual action potentials of dopaminergic cells on a short time-scale (i.e. phasically). Rather, this input appeared to influence DA cell activity on a longer timescale (i.e. tonically) (Overton and Clark, 1997).
2.3.2.2. Cholinergic regulation of VTA dopamine neurons. When considering the finding that the PPTg can also provide excitatory input for midbrain DA neurons it should be kept in mind that this input may not exclusively be mediated by glutamate but may also be carried by acetylcholine. In fact, acetylcholine activation of both, nicotinic and muscarinic receptors on DA neurons causes depolarization and increases in firing rate and bursting (Calabresi et al., 1989; Gronier and Rasmussen, 1998; Sorenson et al., 1998). Thus, although acetylcholine may not be the main driving force of DA neurons and may also not be the ultimate agent responsible for the induction of burst activity, it may
nevertheless facilitate the induction of bursts by other excitatory inputs. That acetylcholine does not have a trivial action in the midbrain is exemplified by the finding that acetylcholine apparently reduces glutamate release via presynaptic muscarinic receptors (Grillner et al., 1999) and increases GABA release via presynaptic muscarinic receptors on striatonigral terminals (Kayadjanian et al., 1994). Thus, in addition to its direct stimulatory actions on DA neurons, acetycholine also has an indirect inhibitory effect, and the net effect of acetylcholine released in the VTA/SN on the activity of DA neurons will depend on a complex interplay with dopaminergic, glutamatergic and GABAergic elements (see Kitai et al., 1999). As mentioned in section 2.2.3.3, cholinergic axon terminals in the VTA appear to target predominantly mesocortical DA neurons (Garzo´n et al., 1999). This observation might be important for the well known, but as yet unexplained, anti-Parkinsonian effects of anticholinergic drugs in animal models and in patients with Parkinson’s disease (PD). If cholinergic input to the VTA is indeed predominantly activating mesocortical DA neurons, then anticholinergic drugs should predominantly reduce activity of those cells. This would reduce inhibitory dopaminergic input to pyramidal cells in the mPFC, thus enhancing activity of prefrontal cortical excitatory efferents to the VTA, which would in turn lead to enhanced activity of the remaining dopaminergic neurons projecting to the NAS, and thus produce an anti-Parkinsonian effect. This scenario is of course highly speculative and is difficult to reconcile with several demonstrations that nicotinic as well as muscarinic agonists activate dopaminergic cells in the VTA, and produce locomotion and reward (Grenhoff et al., 1986; Mereu et al., 1987; Calabresi et al., 1989; Corrigall and Coen, 1989; Lacey et al., 1990; Museo and Wise, 1990, 1994a,b, 1995; Corrigall et al., 1994; Nisell et al., 1994a,b; Panagis et al., 1996; Pidoplichko et al., 1997; Yeomans and Baptista, 1997; Gronier and Rasmussen, 1998). Nicotinic as well as muscarinic acetylcholine receptors have been shown to be located on dopaminergic cells in the VTA (Clarke and Pert, 1985; Goldner et al., 1997), but to our knowledge it has not been determined whether these receptors are located on mesolimbic or on mesocortical DA neurons. If one assumes that receptors are mainly associated with synaptic contacts, the findings of Garzo´n et al. (1999) would imply that these receptors are located on mesocortical neurons. However, if cholinergic receptors were more evenly distributed on both mesocortical and mesolimbic neuron populations, then it could be the case that in the intact animal the stimulatory cholinergic input on mesolimbic neurons ‘outweighs’ the effect on mesocortical neurons (which would, via increased inhibitory input to the mPFC, decrease glutamatergic excitatory input to the VTA and would thus act to
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decrease NAS DA release), such that overall cholinergic stimulation of the VTA would result in increased NAS DA release, locomotion and reward. There is evidence that at least during the early stages of PD, in addition to the degeneration of the nigrostriatal projection, mesolimbic DA neurons are affected to a greater degree than mesocortical DA neurons (Forno, 1990). Thus, it could be that under pathological conditions behavioral and neurochemical effects of cholinergic drugs in the VTA are no longer primarily mediated via mesolimbic DA neurons but rather by mesocortical DA neurons. If this was indeed the case, then in the Parkinsonian brain anticholinergic drugs would act predominantly on mesocortical neurons, leading to effects as outlined above. Another mechanism by which nicotine could activate mesoaccumbal DA neurons despite the apparent relative scarcity of cholinergic input to these cells is via presynaptic facilitation of glutamate release in the VTA from terminals of mPFC afferents (see Vidal, 1994; Wonnacott et al., 1996; Schilstro¨m et al., 1998). Clearly, more work needs to be done to resolve these issues. Amongst other things, it would be interesting to determine how anticholinergics affect dopaminergic transmission in the mPFC and glutamatergic transmission in the VTA in intact and in 6-OHDA lesioned animals, or the exact relationship of cholinergic terminals with dopaminergic cells in the SN, since the nigrostriatal projection is also, and even more importantly involved in Parkinson’s disease.
2.3.2.3. The role of VTA GABAergic neurons. Electrical and chemical stimulation of the mPFC induces release of glutamate, DA and CCK in the striatum and NAS (Taber and Fibiger, 1993, 1995; Taber et al., 1995; Karreman and Moghaddam, 1996; Lada et al., 1998; You et al., 1998). The source of glutamate and CCK most likely are the direct projections originating in the mPFC (Godukhin et al., 1980; Young and Bradford, 1986; Palmer et al., 1989; Perschak and Cuenod, 1990; Lada et al., 1998; You et al., 1998). The release of glutamate is regulated by metabotropic glutamate receptors located presynaptically on glutamatergic terminals, although the mechanisms of this presynaptic regulation and the precise involvement of the different mGluR subtypes is not yet entirely clear (Lovinger et al., 1993; Taber and Fibiger, 1995; Tyler and Lovinger, 1995; Lada et al., 1998). A closer look at the anatomical organization of the circuits involved may resolve the apparent paradox that stimulation of the mPFC induces DA release in the NAS despite the fact that glutamatergic afferents to the VTA have been shown to synapse predominantly on non-dopaminergic cells (i.e. presumably GABAergic neurons) in the VTA (Sesack and Pickel, 1992; Wang and French, 1995). Activation of these GABAergic cells
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would be expected to have an inhibitory effect on dopaminergic cells, which is incompatible with the observed increase in DA release in the NAS. However, given that a GABAergic projection from the VTA to the NAS/striatum also exists (van Bockstaele and Pickel, 1995) which terminates predominately on cholinergic interneurons (Pickel and Chan, 1990), it might be that the glutamatergic prefrontal cortical input to the VTA terminates predominantly not on GABAergic interneurons that would in turn inhibit dopaminergic neurons but rather on those GABAergic cells that project to subcortical targets. This would inhibit the cholinergic interneurons in NAS/striatum, thus decreasing excitatory cholinergic input to medium spiny neurons. In addition to this ‘indirect’ mechanism the ‘direct’ mPFC-VTA-NAS pathway would be responsible for the DA release observed in the NAS after mPFC stimulation. This outlined scenario may also explain why the rewarding effects of mPFC self-stimulation appear to be mediated via glutamatergic transmission in the VTA yet seem to be relatively independent of dopaminergic mechanisms (see section 3.1.3). Yet another scenario is possible. Stimulation of the mPFC is likely to result in activation of the glutamatergic cortico-accumbal projection (Tzschentke et al., 1997; You et al., 1998). Glutamate released in the NAS would activate GABAergic spiny neurons. Since these neurons project to the ventral pallidum, but also to the VTA, mPFC stimulation would ultimately lead to increased GABA release in the VTA. Assuming that GABA would predominantly act on GABAergic interneurons, this would relieve DA neurons from GABAergic inhibition, thus leading to enhanced DA release in the NAS. Of course, this mechanism is speculative and awaits experimental testing. It is also not consistent with the observation that the effects of mPFC stimulation on NAS DA release can be blocked by intra-VTA blockade of glutamate receptors (see references above), since this mechanism would require the action of GABA rather than glutamate in the VTA.
2.3.3. Dopamine–glutamate–GABA interactions in the NAS 2.3.3.1. Glutamatergic regulation of accumbal spiny neurons. When discussing the possible relevance of the corticoaccumbal/corticostriatal projection for behavioral output it should be kept in mind that this may crucially depend upon whether this glutamatergic input targets NMDA- or AMPA receptors. As outlined below, NMDA receptor blockade at the level of the NAS/striatum clearly has stimulatory effects on behavior. By implication (Schmidt and Bury, 1988) activation of NMDA receptors in the NAS/striatum should reduce behavioral output. Interestingly, the effect medi-
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ated via AMPA receptors appears to be quite the opposite to that of NMDA receptors. Thus, moderate doses of AMPA injected into the NAS or striatum produce behavioral activation (Boldry et al., 1993; Svensson et al., 1994b). Conversely, in studies using systemic injections of the AMPA antagonists NBQX or GYKI52466 it was found that although these drugs had only very minor effects on spontaneous behavior (Danysz et al., 1994; Bubser et al., 1995), they did not have anti-cataleptic effects in DA-antagonist induced catalepsy (Papa et al., 1993; Zadow and Schmidt, 1994) (in contrast to NMDA receptor antagonists) and even increased raclopride-induced catalepsy (Papa et al., 1993), and attenuated the locomotor stimulant and anticataleptic effects of MK-801 (Hauber and Andersen, 1993; Bubser et al., 1995).
2.3.3.2. Glutamatergic regulation of accumbal dopaminergic afferents. As mentioned above, the mPFC importantly influences dopaminergic neurotransmission at the axon terminal level in the NAS as well as at the cell body level in the VTA. Prominent mutual DA – glutamate interactions exist in the NAS/striatum (Hirata et al., 1984; Cheramy et al., 1986; Kornhuber and Kornhuber, 1986; Kerkerian et al., 1987; Maura et al., 1988; Clow and Jhamandas, 1989; Kalivas et al., 1989; Halpain et al., 1990; Imperato et al., 1990a,b; GarciaMunoz et al., 1991; Lonart and Zigmond, 1991; Ohta et al., 1994), although how exactly glutamate affects dopaminergic transmission (facilitatory versus inhibitory actions, effects on basal versus evoked release of DA, action via NMDA, AMPA/kainate or metabotropic receptors) is not absolutely clear in all aspects. In particular, whether physiological levels of glutamate in the NAS/striatum can increase the release of DA by acting on presynaptic NMDA or AMPA receptors located on dopaminergic terminals (Krebs et al., 1991a,b) is still a matter of debate (see e.g. results and discussion in Romo et al., 1986; Imperato et al., 1990a,b; Keefe et al., 1992; Westerink et al., 1992; Youngren et al., 1993; Ohta et al., 1994). It has been argued that the DA release that is seen only after relatively high doses of glutamate or glutamate agonists represents a non-physiological effect (Svensson et al., 1994b), although quite the opposite effect, i.e. an increase in extracellular levels of DA by low and a decrease of extracellular levels of DA by high doses of glutamate has also been observed (Cheramy et al., 1986; Leviel et al., 1990). The picture is further complicated by the finding that local administration of glutamate receptor antagonists into the NAS also increases extracellular levels of DA (Imperato et al., 1990b; Keefe et al., 1992; Taber and Fibiger, 1995). The available anatomical data does not directly help to resolve this issue since it has been found that the terminals of mPFC efferents in the NAS are often in close apposi-
tion with dopaminergic terminals, but they do not form direct axo-axonic synapses with dopaminergic terminals (Bouyer et al., 1984; Freund et al., 1984; Sesack and Pickel, 1992). Thus, although a direct, ‘point-to-point’ influence of glutamatergic input on the release of DA is not likely based on these anatomical findings, it could nevertheless be possible that extrasynaptic glutamate acts on dopaminergic terminals (‘volume transmission’) (Wightman and Zimmerman, 1990; Zoli et al., 1999). Vice versa, D2 receptors have been shown to be located on the axon terminals of pyramidal cells projecting to the NAS/striatum (Filloux et al., 1988), thus extrasynaptic DA could also potentially affect the release of glutamate at the level of the NAS/striatum. The glutamatergic projection to the NAS does probably not mediate the increase in extracellular DA in the NAS induced by stimulation of the mPFC (e.g. by presynaptically stimulating DA release from dopaminergic terminals in the NAS). In fact, at least for the striatum it has been shown that the large majority of NMDA receptors is located on striatal (spiny) neurons and not on corticostriatal or nigrostriatal terminals (Albin et al., 1992; Wu¨llner et al., 1994a,b). Rather, as mentioned previously, the stimulatory effect of electrical or chemical stimulation of the mPFC on DA release in the NAS appears to mediated by excitatory corticofugal projections to the VTA acting on ionotropic glutamate receptors (Seutin et al., 1990; Suaud-Chagny et al., 1992; Chergui et al., 1993; Wang and French, 1993a,b; White, 1996; Takahata and Moghaddam, 1998) or other structures such as the PPTg which in turn projects back to and excites dopaminergic neurons in the VTA (Scarnati et al., 1986; Di Loreto et al., 1992). Nevertheless, glutamate in the NAS appears to be involved in the regulation of basal DA levels in the NAS/striatum via its action on metabotropic glutamate receptors (Verma and Moghaddam, 1998).
2.3.3.3. Dopaminergic regulation of accumbal glutamatergic afferents. As outlined in the preceding section, glutamate can regulate DA release at the level of the NAS. There is data to suggest that the reverse is also the case, i.e. that dopamine can regulate or at least modulate glutamate release at the level of the NAS. For example, Dalia et al. (1998) have shown that not only systemic but also intra-NAS administration of amphetamine increases extracellular levels of glutamate in the NAS. This effect was blocked by either the D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride. The effect was mimicked by intraNAS co-administration of the D1 receptor agonist SKF38393 and the D2 receptor antagonist quinpirole, but not by either drug alone. However, the results of a number of control experiments led these authors to conclude that the NAS glutamate release caused by DA agonists is neither sufficient nor necessary to produce a
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stimulation of locomotor activity, i.e. the observed increase in glutamatergic transmission appeared to be merely a ‘side effect’ of DA receptor stimulation that was of no direct behavioral relevance. How DA or DA agonists locally increase glutamate levels in the NAS is not clear. A direct, presynaptic stimulatory action on glutamatergic terminals seems unlikely in light of the observation that, at least in the striatum, stimulation of DA receptors attenuates rather than stimulates glutamate release (Rowlands and Roberts, 1980; Godukhin et al., 1984; Maura et al., 1988; Yamamoto and Davy, 1992), although it has been argued that at the level of the VTA D1 receptor agonists can stimulate glutamate release via action on D1 receptors located presynaptically on prefrontal cortical afferents (Kalivas, 1995; Kalivas and Duffy, 1995; Lu et al., 1997b). Alternatively, the effects of DA receptor activation may be mediated via ‘long-loop’ circuits, such that dopaminergic inhibition of striatal or accumbal projection neurons ultimately results in increased activation or decreased inhibition of glutamatergic projections to the striatum or NAS. Strikingly, almost the opposite findings to those of Dalia et al. (1998) described above have been reported by Kalivas and Duffy (1997). Here, intra-NAS infusion of amphetamine reduced levels of extracellular glutamate. This effect was mimicked by the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF82958, and was blocked by SCH23390 and the D2 receptor antagonist sulpiride. The reason for these contrary findings is not clear but may be related to the use of very different drug concentrations in these two studies. While Dalia et al. (1998) infused 10 mM amphetamine, 20 mM SKF38393 and 50 mM quinpirole, the maximum concentration of amphetamine, SKF82958 and quinpirole infused by Kalivas and Duffy (1997) was 100 mM. Thus, Dalia et al. (1998) used concentrations at least 100-fold higher than those used by Kalivas and Duffy (1997). The higher drug doses used by Dalia et al. (1998) could have lost their specificity for the DA transporter and DA receptors. The view that the effects in that study may have been non-specific is also supported by the fact that the results obtained by Kalivas and Duffy (1997) using much lower doses are completely in line with the inhibitory effects of DA on glutamate release in the striatum found in the studies cited above. Taken together, these findings suggest that, as in the striatum, DA in the NAS acts via presynaptic DA receptors (presumably predominantly of the D2 receptor type) to reduce the release of glutamate, which is also consistent with the histological and electrophysiological evidence for the presence of D2 receptors on corticostriatal terminals (Schwarcz et al., 1978; Brown and Arbuthnott, 1983; Filloux et al., 1988; GarciaMunoz et al., 1991).
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2.3.4. The ‘in6erse’ relationship between cortical and subcortical dopamine In the preceding sections, numerous differences between prefrontal cortical and subcortical DA with respect to functional aspects were described. In the following sections of this review, differences between prefrontal cortical and subcortical DA will be discussed on the behavioral level. In many cases, such differences on the behavioral level are paralleled by differences at the neurochemical level. Thus, many of the different functional effects DA produces in mPFC and NAS/ striatum can more or less directly be correlated with specific neurochemical events. With respect to neurochemistry the general picture parallels the one found for motor activity. Increasing dopaminergic transmission within the mPFC leads to a decrease of dopaminergic activity in the NAS, and decreasing mPFC dopaminergic transmission produces increased levels of dopaminergic activity in the NAS. Intra-mPFC injections of amphetamine, cocaine or apomorphine decreased the levels of DA and DA metabolites in the NAS while the injection of a DA antagonist had the opposite effect (Louilot et al., 1989; Jaskiw et al., 1991b; Kolachana et al., 1995). Further evidence for the reciprocal relationship of prefrontal and subcortical DA transmission comes from the finding of Hedou et al. (1999) that after systemic injection of cocaine DA levels in mPFC and NAS showed a significant negative correlation. Unfortunately, the data on the effects of 6-OHDA lesions of the mPFC are less consistent. Such lesions have been shown to enhance K+-stimulated DA release (Thompson and Moss, 1995) and basal extracellular levels of DA and its metabolites in the NAS/striatum (Carter and Pycock, 1978, 1980; Pycock et al., 1980a,b; MartinIverson et al., 1986; Leccese and Lyness, 1987; Haroutunian et al., 1988; Louilot et al., 1989; Kurachi et al., 1995) and also to increase local blood flow in NAS and striatum, an indication of increased metabolic activity (Suzuki et al., 1995). However, a considerable number of studies failed to demonstrate a lesion-induced increase in basal levels of DA or its metabolites after 6-OHDA lesion of the mPFC (Joyce et al., 1983; Dunn et al., 1984; Oades et al., 1986; Swerdlow et al., 1986; Clarke et al., 1988; Bubser and Schmidt, 1990; Schenk et al., 1991; Hemby et al., 1992b; Jones and Robbins, 1992; Rosin et al., 1992; Bubser, 1994; Bubser and Koch, 1994; Sokolowski and Salamone, 1994; Banks and Gratton, 1995; King and Finlay, 1995; McGregor et al., 1996). King and Finlay (1995) also reported that 6-OHDA lesions of the mPFC did not affect the ability of amphetamine to increase extracellular DA in the striatum. On the other hand, Beyer and Steketee (1999) reported that 6-OHDA lesions of the mPFC significantly enhanced the effects of cocaine on extracellular levels of DA in the NAS.
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One possible explanation for the inconsistent findings for 6-OHDA lesions may come from the results of King et al. (1997) who found that 6-OHDA lesions of the mPFC have differential effects on dopaminergic transmission in NAS core and shell. In that study it was found that such lesions did not affect basal DA and stress-induced increase in extracellular DA levels in the core but increased basal DA levels and potentiated the stress-induced DA release in the shell of the NAS. Conversely, the lesions did not alter the ability of systemic amphetamine to increase DA release in the shell but attenuated the amphetamine effect on extracellular DA in the core of the NAS. Because the anatomical, pharmacological, physiological and functional characteristics of the core and shell subareas of the NAS have only been described beginning in the late 1980s (Zaborszky et al., 1985; Voorn et al., 1986, 1989; Zahm and Heimer, 1988, 1993; Zahm, 1991; Berendse et al., 1992; Deutch and Cameron, 1992; Brog et al., 1993), a distinction between core and shell has not been made in most of the earlier studies. Relating to the functional heterogeneity of the mPFC (see section 4), it may be that 6-OHDA lesions of the mPFC in many studies have affected the different subareas to a differential degree, thus differentially affecting DA transmission in NAS core and shell. To the extent that core and shell mediate different behaviors, this would lead to different, ‘inconsistent’ neurochemical effects for the NAS as a whole as well as to ‘inconsistent’ behavioral output (see below). One point to be kept in mind when discussing the subcortical effects of cortical lesions is the extensive collateralization of the mPFC output neurons (Ferino et al., 1987). Thus, manipulations of the mPFC do not only directly affect one given subcortical target area of mPFC efferents but also other subcortical areas, which may then in turn also affect neurochemical or electrophysiological activity in that given subcortical area. Given the complexity of the basal ganglia – thalamocortical circuits in which mPFC efferents are only one of many elements, it may be very difficult to understand and explain the effects of mPFC manipulations on a given subcortical area without consideration of other structures which are also potentially affected by this manipulation. A ‘systems’ approach may therefore be a very important and powerful addition to the focused examination of individual structures in the study of the function of the mesocorticolimbic system. As mentioned above, on a functional level, prefrontal cortical DA appears to exert an inhibitory influence on mesoaccumbens dopaminergic transmission. 6-OHDA lesions of the mPFC were shown to increase the sensitivity of the mesoaccumbal DA projection to footshock stress, i.e. low-intensity footshocks that did not have an effect on NAS DA release in control animals were sufficient to produce a significant release of DA in the
NAS (but not in the dorsal striatum) in lesioned animals (Deutch et al., 1990); likewise, the magnitude of DA release in the NAS induced by a given stressor intensity was larger in animals bearing 6-OHDA lesions of the mPFC as compared to nonlesioned controls (King et al., 1997). This lesion effect seems to be specific for the NAS since similar 6-OHDA lesions of the mPFC did not affect DA release in the neostriatum induced by tail-pressure stress (King and Finlay, 1995). The effect of mPFC DA depletion on subcortical DA responses to stimuli does not seem to be restricted to stress. Rosin et al. (1992) demonstrated that 6-OHDA lesions of the mPFC potentiated the haloperidol-induced increase in tyrosine hydroxylase activity in the NAS, and Mitchell and Gratton (1992) showed that partial DA depletion in the mPFC also enhanced the mesolimbic DA release induced by repeated exposure to naturally reinforcing stimuli such as food or sucrose solution. Thus, it seems as if DA in the mPFC ‘dampens’ the effects of aversive (e.g. stress) as well as rewarding (e.g. food) stimuli on subcortical DA systems, acting as some kind of ‘negative feedback’. A disruption of this inhibitory control in the mPFC might contribute to the exacerbation of symptoms by stress in schizophrenic patients (Weinberger, 1987) or to an increased vulnerability to the addictive effects of drugs (Deminie`re et al., 1988, 1989; Piazza et al., 1991) (see also sections 3.1.4 and 3.4). GABAergic activity in the mPFC and NAS also seems to be differentially regulated by DA. Re´taux et al. (1994) showed that DA denervation by bilateral electrolytic lesions of the VTA resulted in a decrease in GAD67 mRNA levels (glutamic acid decarboxylase, the marker enzyme for GABAergic cells) in the prelimbic area of the mPFC but caused an increase in GAD67 mRNA levels in the shell of the NAS. From this it can be concluded that under physiological conditions DA in the mPFC tonically stimulates GAD67 mRNA expression and thus, presumably, GABAergic activity, while in the NAS shell DA tonically inhibits GAD67 mRNA expression and GABAergic activity. This conclusion is in line with neurochemical and electrophysiological findings that DA in the mPFC generally increases spontaneous GABA release and spontaneous firing of GABAergic neurons (Penit-Soria et al., 1987; Re´taux et al., 1991a,b) and that DA in the NAS generally inhibits the activity of GABAergic spiny neurons (Wilson, 1995). Interestingly, these differences appear to hold only with respect to the basal release of GABA, since electrically- or K+-evoked GABA release is blocked by D2 receptor activation in the mPFC (Re´taux et al., 1991a) as well as in the striatum (Tossman and Ungerstedt, 1986; Bernath and Zigmond, 1989). Taken together, these results suggest that in the mPFC DA exerts a (tonic) stimulatory effect on GABAergic interneurons
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(thereby inhibiting glutamatergic pyramidal cells projecting to the NAS and VTA) whereas in the NAS DA has inhibitory effects on GABAergic spiny neurons. How DA can exert excitatory as well as inhibitory effects via D2 receptors, which are generally coupled to Gi-proteins that inhibit the activity of adenylate cyclase (Seeman and van Tol, 1994), is an unresolved issue. DA release in the NAS and the mPFC has also been shown to be differentially affected by antidepressant drugs of different pharmacological classes and also by a number of non-psychostimulant drugs of abuse. Thus, it has been shown that a clear DA release in the mPFC was induced by doses of antidepressant drugs had no or only small effects on DA release in the NAS (Carboni et al., 1990; Di Chiara et al., 1992; Tanda et al., 1994, 1995, 1996). On the other hand, morphine, nicotine, and ethanol were much more potent in increasing extracellular levels of DA in the NAS as compared to the mPFC (Bassareo et al., 1996). It should be noted, however, that Noel and Gratton (1995) found that intra-VTA injection of the m-receptor agonist DAMGO resulted in DA release of the same magnitude in NAS and mPFC (if anything, the effect in the mPFC tended to be more pronounced and longer-lasting). An observation that may be of relevance for the action of antidepressants and antipsychotics considered in the context of mPFC function is that a2-receptor antagonists markedly increase DA release in the mPFC, an effect that is not seen in the NAS/striatum, and that probably is mediated at the DA nerve terminal level in the mPFC, independently of impulse flow in dopaminergic neurons (Gresch et al., 1995a; Tanda et al., 1996; Gobert et al., 1998; Yamamoto and Novotney, 1998; Hertel et al., 1999). Since ‘atypical’ antipsychotics such as clozapine or risperidone or ‘atypical’ antidepressants such as mianserin or mirtazapine block a2 receptors with relatively high affinity, it has been suggested that this pharmacological property of these drugs contributes to their therapeutic effects (van Dorth, 1983; Nutt, 1994; Davis and Wilde, 1996; Litman et al., 1996; Schotte et al., 1996; Hertel et al., 1997). In any case, the preferential effects of a2-receptor antagonists on mPFC DA release versus NAS DA release are consistent with the relatively high density of a2-receptors in the mPFC (Talley et al., 1996) and the apparent absence of these receptors in the NAS (Schoffelmeer et al., 1998).
3. Behavioral pharmacology of the mesocortical dopamine system
3.1. Reward While an almost overwhelmingly large literature exists concerning the role in reward and reinforcement processes of the VTA and the NAS in general and of
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the mesoaccumbal DA system in particular (for reviews see Koob, 1992; Di Chiara, 1995; Salamone, 1996; Wise, 1996a; Bardo, 1998; Beninger and Miller, 1998; Ikemoto and Panksepp, 1999), the role in reward of the mPFC in general and of prefrontal cortical DA in particular has received considerably less attention and remains rather elusive to date. Nevertheless, there is good evidence that mPFC neurons are involved in reward mechanisms in the brain, although the role of DA in this context is not very well defined (for review, see Tzschentke, 2000).
3.1.1. Conditioned place preference In the conditioned place preference paradigm (CPP), the treatment in question is repeatedly paired with a set of distinct environmental cues, while a neutral control treatment is repeatedly paired with a different set of distinct environmental cues. If the treatment in question is rewarding for the animal, it will, during this repeated pairing, associate these rewarding effects with the distinct environmental cues paired with the treatment. Subsequently, these conditioned, secondary-reinforcing cues will elicit approach behavior, and the animal will thus show a preference for these cues over the neutral cues when given a free choice between them (van der Kooy, 1987; Carr et al., 1989; Tzschentke, 1998). A particular role of the mPFC for cocaine reward effects is seen in place preference studies. While cocaine injected into the mPFC produces CPP (Hemby et al., 1990), amphetamine (Carr and White, 1986; Schildein et al., 1998) as well as morphine and the m-opioid receptor agonist DAMGO (Bals-Kubik et al., 1993; Olmstead and Franklin, 1997) injected into the mPFC fail to do so. Interestingly, the opposite is true for injections of the drugs into the NAS (van der Kooy et al., 1982; White et al., 1985; Hemby et al., 1992a; Olmstead and Franklin, 1997) (see Tzschentke, 1998, for a recent review of available CPP data). On the other hand, it has been shown that 6-OHDA lesions of the mPFC, in contrast to the effects of these lesions on intra-mPFC self-administration of cocaine (see below), did not affect the place preference conditioning induced by systemically administered cocaine (Hemby et al., 1992b) and morphine (Shippenberg et al., 1993), showing that reward can be produced by systemically administered drugs independently of prefrontal cortical DA. However, although the rewarding effects of drugs may be independent of prefrontal cortical DA, they may nevertheless depend on overall mPFC function. This is suggested by the finding that quinolinic acid-induced lesions of the mPFC, and even of specific subareas of the mPFC, can block cocaine-, morphine- and CGP37849-induced CPP (Tzschentke and Schmidt 1998a,b, 1999). In these experiments, by including an additional test with drugged animals, it was possible to exclude the possibility that the lesions
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made the acquired CPP state-dependent. In other studies it was shown that mPFC lesions did not affect stimulus-reward learning in classical and operant conditioning paradigms (Isaac et al., 1989; Burns et al., 1993; Bussey et al., 1996) leaving a reduction/blockade of the rewarding effects of the drugs by the mPFC lesions as the most likely interpretation of the CPP results. Another issue to be considered when discussing the effects of drugs or lesions on CPP, especially in cases where the development of CPP was blocked by lesions of or drug injections into the mPFC, is that an observed blockade of CPP might not be due to the disruption of the primary rewarding effects of the drugs or to the disruption of conditioning, but might rather be due to a disruption of the discriminative stimulus properties of the drugs used to establish CPP. Unfortunately, although an extremely large drug discrimination literature exists, only very few studies have addressed the question of which central sites mediate the discriminative stimulus properties of drugs, and apparently nothing is known about the role of the mPFC. Nevertheless, the existing data appears to suggest that structures other than the mPFC may be responsible for the mediation of the stimulus properties of morphine (Jaeger and van der Kooy, 1993; Shoaib and Spanagel, 1994), amphetamine (Nielsen and Scheel-Kru¨ger, 1986; Druhan et al., 1993) and cocaine (Callahan et al., 1997). No relevant data seem to exist for NMDA receptor antagonists. In any case, although no direct evidence exists, it would appear unlikely that the mPFC is involved in the mediation of the discriminative stimulus properties of drugs to the extent that lesioning or pharmacological manipulation of this area would disrupt CPP.
3.1.2. Self-administration In self-administration experiments an animal is implanted with an intravenous catheter or an injection canula directly into a discrete brain region. If a peripheral or central drug injection is experienced as rewarding by the animal, it will learn to perform an operant response (usually lever-pressing or nose-poking) to obtain drug injections (Koob and Goeders, 1989; Richardson and Roberts, 1996). One line of evidence suggesting a role of the mPFC in reward derives from electrophysiological and electrochemical recordings during drug self-administration behavior. When activity of mPFC cells was recorded during drug self-administration, it was found that the firing of mPFC cells can be very closely time-locked to the i.v. injections of cocaine and heroin (Chang et al. 1997a,b, 1998). Likewise, when DA release in the mPFC was monitored during response-contingent delivery of liquid reward using voltammetry, it was found that the DA signal or DA cell activity showed changes time-locked to the delivery of the reward (Richardson
and Gratton, 1998). Qualitatively quite similar timelocked responses have also been found in prefrontal cortical cells of the monkey in an equivalent experimental task (Ono et al., 1984; Watanabe, 1996). Interestingly, in the study of Richardson and Gratton (1998) DA responses were minor when animals consumed a standard reward under a continuous reinforcement schedule but were particularly evident under delayed reinforcement and unexpectedly altered reinforcement conditions. With delayed reinforcement, lever presses were followed by DA signal increases during the delay period and subsequent decreases in the DA signal after the reward had been delivered. Withholding expected reward or delivering a smaller or greater than expected reward also resulted in DA signal increases. Based on these results, the authors suggested that ’’the DA input to PFC is activated when rewards are presented under conditions that deviate from those that the animals had come to expect, particularly so when the temporal structure of learned associations is altered’’ (Richardson and Gratton, 1998, p. 9130). These results are in striking accordance with the findings of Schultz and collegues for the firing behavior of VTA DA neurons under different reinforcement conditions. Here, responses were found to be negligible when familiar rewards were earned and consumed under standard conditions but were found to be most pronounced when a new, unexpected reward or a change in the reinforcement contingencies (withholding an expected reward, delaying reward delivery or delivering the reward earlier than expected, diminishing or increasing the reward magnitude) was encountered (Ljungberg et al., 1992; Schultz, 1986; Schultz et al., 1993, 1997; Guigon et al., 1995). It is tempting to assume that changes in dopaminergic transmission in the mPFC as shown by Richardson and Gratton (1998) are a direct consequence of the alterations in DA cell firing as demonstrated by Schultz and collegues, and that, in turn, the alterations in mPFC pyramidal cell firing as shown by Ono et al. (1984) and Watanabe (1996) are a consequence of alterations of dopaminergic transmission in the mPFC. Unfortunately, although quite extensive mircodialysis data exists about the consequences of drug self-administration on NAS DA levels (e.g. Gratton and Wise, 1994; Wise et al., 1995a,b), apparently no comparable data are available for the mPFC.
3.1.2.1. Intracranial self-administration. Evidence that an elevation of extracellular DA within the mPFC has direct rewarding effects is limited. Thus, it has been shown that cocaine and DA itself is self-administered into the mPFC (Goeders and Smith, 1983, 1986, 1993; Goeders et al., 1986) but not into the NAS (Goeders and Smith, 1983), whereas, surprisingly, the reverse is true for amphetamine, i.e. amphetamine is self-adminis-
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tered into the NAS (Hoebel et al., 1983) but not into the mPFC (Goeders et al., 1986). Co-infusion of the D2 receptor antagonist sulpiride attenuated and 6-OHDA lesions of the mPFC abolished intra-mPFC self-administration of cocaine while the D1 receptor antagonist SCH23390, the beta-noradrenergic receptor antagonist propranolol and the muscarine receptor antagonist atropine were without effect (Goeders and Smith, 1983, 1986; Goeders et al., 1986), pointing to a pivotal role of DA in the mPFC for the rewarding effects of locally injected cocaine that is mediated primarily by D2 receptors. Nevertheless, mechanisms including other transmitters such as noradrenaline or serotonin cannot be completely excluded based on these findings, particularly since cocaine also blocks the reuptake of noradrenaline and serotonin (Yu and Smith, 1977; Taylor and Ho, 1978; Hadfield et al., 1980) and since complex interactions between the various transmitters within the mPFC have been described (see sections above). Another point that has to be considered, especially in the light of the observation that amphetamine, which is self-administered into the NAS (Hoebel et al., 1983), does not sustain self-administration into the mPFC (Goeders et al., 1986) is that the rewarding actions of cocaine may be due to its local anesthetic effects. If inhibition/inactivation of mPFC efferents was an important element in the mediation of reward, then cocaine, due to its local anesthetic properties, would be expected to produce reward independently of its effects on extracellular DA. However, the results of Goeders et al. (1986) suggest that the local anesthetic properties of cocaine are not responsible for its rewarding effects in the mPFC since the cocaine effect was not mimicked by local infusion of lidocaine. Nevertheless, this does not necessarily exclude the possibility that the lack of selfadministration of cocaine into the NAS is due to its local anesthetic properties in addition to and in combination with its other pharmacological properties. We are unaware of any reports addressing this question directly, e.g. by combining amphetamine (which is selfadministered into the NAS) with a local anesthetic such as lidocaine to mimic that particular pharmacological effect of cocaine. Most interestingly, Goeders and Smith, after reviewing their own and other data, conclude that ‘‘these data suggest that cocaine microinjections into the medial prefrontal cortex produce neurochemical and behavioral effects similar to those observed after destruction of the dopaminergic innervations of the prefrontal cortex.’’ (Goeders and Smith, 1993, p. 598). However, how this rather paradoxical effect is mediated remains unknown. One point that might be of relevance in the present context is the fact that intracranial self-administration measures not simply reward per se. Animals perform an operant task in order to earn a drug injection, i.e. they have to be motivated to perform this task. Initially, they have
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learn the association between the operant task and the rewarding effects of the response-contingent drug-infusion, and subsequently they have to recall this association to guide their behavior. Animals also have to make selective responses towards the drug-associated lever and have to suppress other behaviors. Thus, incentive motivation, reward, learning, memory, retrieval of this memory, behavioral inhibition, and response selection are all involved in the acquisition and maintenance of the self-administration behavior, and, as outlined in section 3.4, it is well known that the mPFC plays an important role in working memory and response selection based on temporal contingencies. It might therefore be that the reason why cocaine is self-administered into the mPFC but amphetamine is not lies not in the fact that cocaine produces reward when injected locally and amphetamine does not, but that cocaine, due to some as yet unknown properties, does not interfere with the ‘cognitive functions’ of the mPFC necessary to establish and maintain self-administration behavior, while amphetamine disrupts learning, memory, response selection or some other process important for self-administration. Comparative studies examining the effects of intra-mPFC injections of cocaine and amphetamine in cognitive tasks would be necessary to test this possibility. This interpretation, however, is supported by the findings of Richardson and Gratton (1998) discussed above and also by other evidence suggesting that prefrontal cortical DA is not a reward signal per se, produced by the consumption of a reward, but rather is associated with novelty, ‘excitement’ (i.e. mild stress), expectancy, and operant and classically conditioned responses (D’Angio and Scatton, 1989; Hernandez and Hoebel, 1990; Cenci et al. 1992; Feenstra and Botterblom, 1996; Bassareo and Di Chiara, 1997). It should be noted here, however, that there is some controversy about whether conditioned stimuli elicit DA release within the mPFC. Whereas there is good evidence that food- or drug-associated stimuli can increase DA transmission in the NAS (Phillips et al., 1993; Gratton and Wise, 1994; Richardson and Gratton, 1996), data concerning DA transmission in the mPFC in response to conditioned stimuli is inconsistent. While Richardson and Gratton (1998), Carey and Damianopoulos (1994) found no indication of conditioned DA responses in the mPFC, Bassareo and Di Chiara (1997) showed that stimuli associated with food increased extracellular levels of DA in the mPFC. In studies involving aversive conditioning a conditioned increase in mPFC DA release (Herman et al., 1982; Wedzony et al., 1996; Yoshioka et al., 1996) as well as not effect (Wilkinson et al., 1998) was observed. Since there are several important procedural differences between these studies (voltammetry versus microdialysis, resulting in different sampling area and sampling resolution; classical versus operant condition-
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ing, which may involve different neuronal mechanisms; use of rewarding versus aversive unconditioned stimuli; different handling and habituation procedures, see Feenstra et al., 1999) it is difficult, based solely on these studies, to draw any firm conclusions about the role of the mesocortical DA projection in conditioning processes. Interestingly, the non-competitive NMDA receptor antagonists PCP and MK-801 and the competitive NMDA receptor antagonist CPP are not only self-administered into the NAS shell but also into the mPFC (Carlezon and Wise, 1996a). While in this study it was shown that the self-administration of NMDA-receptor antagonists into the NAS shell was independent of dopaminergic mechanisms (as demonstrated by the failure of sulpiride co-infusion to affect self-administration behavior), unfortunately the same test was not done for the mPFC. Thus, it is not known whether the rewarding effects of NMDA-receptor antagonists when injected into the mPFC are mediated by a local increase in extracellular DA induced by these drugs. However, this possibility seems unlikely for two reasons. Firstly, although PCP at higher doses also has DA uptakeblocking effects, the relatively low doses of PCP used in the above-mentioned study should not be expected to have such an effect. Furthermore, MK-801 and CPP are not known to possess DA uptake-blocking effects. Thus, it seems unlikely that these drugs increase extracellular DA via a local, pharmacologically specific effect. Secondly, given the reciprocal relationship between dopaminergic activity in the mPFC and in the NAS (see section 2.3.4), a mediation via a dopaminergic mechanism would be difficult to explain. Since DA in the mPFC generally inhibits glutamatergic efferents, an increase in mPFC DA would result in reduced excitatory drive to the VTA, and consequently, to reduced DA release in the NAS, which is incompatible with the proposed role of NAS DA in reward mechanisms. Findings that pose considerable interpretational problems have been reported by David et al. (1998). These authors showed that AMPA and NMDA receptor antagonists are self-administered into the VTA, implicating that these injections produced rewarding effects. When self-administration behavior was established peripheral administration of the D2 receptor antagonist sulpiride produced extinction-like responding, indicating that the rewarding effects of the self-administered glutamate antagonists were dependent on dopaminergic neurotransmission, presumably manifest as an increase in NAS DA release. This is incompatible with the notion that the rewarding effects of mPFC stimulation are ultimately mediated by increased glutamatergic activation of VTA DA neurons. It is also incompatible with the observation that at the level of the VTA glutamate agonists rather than antagonists produce burst firing in DA neurons (see section 2.3.2.1).
The finding of David et al. (1998) would implicate that glutamatergic input to the VTA predominantly terminates on inhibitory GABAergic interneurons and that this input exerts, via these interneurons, a tonic inhibitory influence on dopaminergic neurons, such that injection of a glutamate antagonist would reduce excitatory input onto GABAergic neurons and would thus relieve the dopaminergic neurons from tonic GABAergic inhibition. Although this is consistent with the fact that the GABA-A receptor antagonist bicuculline is self-administered into the VTA (David et al., 1997; Ikemoto et al., 1997), it is difficult to reconcile with the numerous findings mentioned in previous sections that glutamatergic input to the VTA has potent excitatory effects on dopaminergic activity (with respect to firing of DA neurons, reward, locomotion). It is also inconsistent with the finding of Mathe´ et al. (1998) that locomotor activity and DA release in the NAS produced by systemic administration of MK-801 was antagonized by intra-VTA infusion of the AMPA/kainate receptor antagonist CNQX. In the same study VTA CNQX infusion itself did not have any behavioral effects and also had no effects on DA levels in the NAS. This apparent ineffectiveness of CNQX is difficult to reconcile with its presumed rewarding effects after intra-VTA injection. A hypothetical scenario that could resolve these apparent inconsistencies would involve presynaptic inhibitory autoreceptors on glutamatergic terminals in the VTA. If this were the case, glutamate antagonists, by blocking these autoreceptors, would increase extracellular glutamate in the VTA which would increase activity of DA neurons and DA release in the NAS, and would therefore have the same effects as glutamate agonists acting directly on postsynaptic glutamate receptors on the cell bodies of DA neurons. To our knowledge experimental evidence for or against this scenario is not available. At least in the striatum and hippocampus glutamate release appears to be under tonic inhibition via NMDAand AMPA receptors, although in this case, too, an indirect mechanism involving GABAergic neurons cannot be excluded (Liu and Moghaddam, 1995). Clearly, much more work is needed to resolve these issues.
3.1.2.2. Lesion effects on intra6enous self-administration. Weissenborn et al. (1997) showed that quinolinic acid lesions of the mPFC facilitated acquisition of cocaine IV self-administration under a fixed ratio schedule. Also, under a second-order schedule of reinforcement lesioned rats showed higher rates and disrupted pattern of responding compared to control rats. This responding was not affected by omission of the conditioned stimulus in the lesioned animals. On the other hand, acquisition of responding for a non-drug reinforcer, sucrose, was not affected by the lesion. The authors interpreted their findings not in terms of an enhancement of cocaine reward by the lesion but in terms of
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deficits in behavioral inhibition induced by the mPFC lesions (see also Ravard et al., 1990; Burns et al., 1993, 1996; Granon et al., 1994; Broersen et al., 1995, 1999; Muir et al., 1996; Jinks and McGregor, 1997; see also section 3.4). According to this interpretation, ‘‘rats with medial prefrontal cortex lesions are more likely than controls to explore the self-administration chamber during the initial stages of testing, approaching the lever that delivers cocaine more frequently, and therefore self-administering more drug during acquisition.’’ (Weissenborn et al., 1997, p. 252). It has also been shown that rather large ibotenic acid lesions of the mPFC did not affect voluntary ethanol intake in rats (Hansen et al., 1995) and that temporary inactivation by injection of lidocaine into the prelimbic subarea of the mPFC did not affect responding in a fixed-interval lever pressing task for food reward (Evans and Cory-Slechta, 2000). On the other hand, relatively large electrolytic lesions of the frontal cortex decreased the reinforcing effects of self-administered morphine (Trafton and Marques, 1971; Glick and Cox, 1978). As shown by Goeders et al. (1986) co-infusion of the D1 antagonist SCH23390 was without effect on intracranial self-administration of cocaine. On the other hand, intra-mPFC injection of SCH23390 was shown to reduce the rewarding effects of i.v. self-administered cocaine (McGregor and Roberts, 1995). Also, 6-OHDA lesions of the mPFC actually enhanced the rewarding effects of intravenously self-administered cocaine in two studies (Schenk et al. 1991; McGregor et al. 1996) while having no effect in another study (Martin-Iverson et al. 1986) and also having no effect on either acquisition or maintenance of i.v. amphetamine self-administration (Leccese and Lyness 1987). The apparent discrepancy between the findings of Goeders and Smith versus McGregor et al. and Schenk et al. regarding the effects of mPFC 6-OHDA lesions on cocaine self-administration may be due to a differential degree of DA depletion at the site of cocaine action within the mPFC, as discussed by Bardo (1998). According to this interpretation, in the Goeders and Smith study, by injecting 6-OHDA through the self-administration canula, a very focussed but complete DA depletion at the site of cocaine action may have been achieved, yielding extinction-like responding although overall DA depletion of the whole mPFC was low. On the other hand, in the other two studies, although 6-OHDA lesions resulted in a higher overall DA depletion in the mPFC, a population of DA axon terminals is likely to have survived, at least at some distance from the site of injection of 6-OHDA. Since after systemic administration cocaine will reach much larger sections of the mPFC than after local injection, cocaine could have acted on these remaining terminals which, together with the presumed denervation supersensitivity of postsynaptic DA recep-
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tors, resulted in an even enhanced rewarding effect of cocaine in the two latter studies. Another point to be considered are the procedural differences between these self-administration studies. Schenk et al. (1991) and McGregor et al. (1996) reported that 6-OHDA lesions of the mPFC enhanced the rewarding effects of low ( 0.1–0.25 mg/kg/inf.), but not of high ( 0.4–1.5 mg/kg/inf.) unit doses of IV cocaine, indicating that drug dose may be an important factor determining the outcome of an experiment. Because of the local route of drug administration it is difficult determine how the doses of cocaine used in the Goeders and Smith study relate to ‘high’ and ‘low’ IV unit doses, but the unit dose used by Martin-Iverson et al. (1986) would fall into the ‘high’ dose category in the studies of Schenk et al. and McGregor et al. which might well explain the lack of lesion effect observed by Martin-Iverson et al. (1986). In addition, further procedural differences between these studies exist. Schenk et al. (1991) tested the lesion effects on the acquisition and maintenance of self-administration behavior under a fixed-ratio schedule of reinforcement, McGregor et al. (1996) tested the lesion effects on maintenance of selfadministration under a progressive-ratio schedule, while Goeders and Smith (1986) and Martin-Iverson et al. (1986) used yet another combination of parameters, in that they tested the effects of the lesions on maintenance under a fixed-ratio condition. These factors make the comparison of these studies quite difficult, and it may be of relevance here that the outcome of a self-administration experiment can actually depend on whether fixed ration or progressive ratio schedules are used. Thus, McGregor and Roberts (1995) found that under an FR1 schedule the D1 receptor antagonist SCH23390 produced an increase in the rate of cocaine intake following injection into either mPFC or striatum; in contrast, under a PR schedule similar injections into the striatum had no effect on the breaking point while large decreases in breaking point were produced by intra-mPFC injections of the drug. This indicates that the two schedules measure different aspects of the reinforcing actions of cocaine. The reason for this is unclear, but it shows that one has to be cautious when comparing results from self-administration studies that have used different schedules of reinforcement (see also McGregor and Roberts, 1993, 1995, for further discussion of this point).
3.1.3. Self-stimulation Perhaps the most obvious evidence that the mPFC participates in brain reward mechanisms is the wellknown observation that the mPFC supports electrical intracranial self-stimulation (ICSS). In intracranial selfstimulation experiments a stimulating electrode is implanted into a discrete brain region. If the electrical stimulation of this region is experienced as rewarding
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by the animal, it will learn to perform an operant response (usually lever-pressing or nose-poking) to obtain this stimulation (Stellar and Rice 1989; Phillips and Fibiger 1989). Although the rates of responding obtained for ICSS in the mPFC are generally lower than the rates obtained for VTA or MFB self-stimulation, very robust and reliable self-stimulation behavior can be obtained with electrodes in the mPFC. Although this phenomenon has long been known and has received a lot of interest (Routtenberg and Sloan, 1972; Mora, 1978; Phillips and Fibiger, 1978; Ferrer et al., 1983; Mora and Ferrer, 1986; Mora and Cobo, 1990), the underlying neurophysiological and neuropharmacological mechanisms are still somewhat elusive. While VTA or MFB ICSS is not affected by 6-OHDA lesions or by injection of neuroleptics into the mPFC (Mogenson et al., 1979; Simon et al., 1979b), it seems well established that the rewarding effects of VTA and MFB self-stimulation involve subcortical dopaminergic mechanisms (e.g. Fouriezos et al., 1978; Phillips and Fibiger, 1978; Mogenson et al., 1979; Fibiger et al., 1987; Gratton et al., 1988; Phillips et al., 1989; Nakahara et al., 1989a,b, 1992; Manley et al., 1992; Fiorino et al., 1993; but see Gallistel, 1986; Miliaressis et al., 1991; Bauco et al., 1994; Hunt and McGregor, 1998 for findings that question the role of DA as the ultimate mediator of MFB or VTA ICSS). On the other hand, there is considerable disagreement in the literature about the extent to which mPFC ICSS is dependent upon dopaminergic mechanisms. Early studies have demonstrated a rather striking overlap between those regions of the prefrontal cortex that sustain ICSS (Routtenberg and Sloan, 1972) and those regions of the prefrontal cortex that receive a dense dopaminergic innervation (Thierry et al., 1976b). Furthermore, mPFC ICSS has been shown to clearly increase DA release in the same region (Mora, 1978). From these observations it seemed intuitive to assume that the ability of prefrontal cortical regions to sustain ICSS is somehow linked to its dopaminergic innervation. However, behavioral and pharmacological evidence for this assumption is inconsistent, with respect to the role of prefrontal cortical DA as well as with respect to the role of DA in general. Some studies have shown that the rewarding effects of the stimulation (in terms of rates of responding) can be decreased by administration of DA antagonists and increased by administration of DA agonists (Phillips and Fibiger, 1978; Robertson and Mogenson, 1978; Ferrer et al., 1983; Hand and Franklin, 1983; Moody and Frank, 1990; Mora and Cobo, 1990; McGregor et al., 1992; Sabater et al., 1993), but other studies showed a relative independence of mPFC ICSS of dopaminergic mechanisms in comparison to MFB or VTA ICSS (Carey et al., 1975; Mora et al., 1977; Phillips and Fibiger, 1978; Mogenson et al., 1979; Simon et al., 1979b; Robertson et al., 1981; Phillips et al., 1987, 1992; Nakahara et al.,
1989b; Corbett, 1990; Singh et al., 1997). Chemical (Murase et al., 1993a; Karreman and Moghaddam, 1996) and electrical (Taber and Fibiger, 1993, 1995; Taber et al., 1995; You et al., 1998) stimulation as well as electrical self-stimulation of the mPFC (You et al., 1998, Tzschentke et al. unpublished observations) increases extracellular levels of DA in the NAS. If this stimulation-induced increase in NAS DA is blocked by intra-VTA infusion of the glutamate receptor antagonist kynurenic acid (presumably by blocking the excitatory glutamatergic input from prefrontal cortical afferents onto DA cell bodies), self-stimulation behavior is not sustained, indicating that the stimulation has lost its rewarding effects (You et al., 1998, Tzschentke et al., unpublished observations). These findings would argue that DA does have a role in the mediation of the rewarding effects of mPFC ICSS. When considering the effects of DA antagonists on mPFC ICSS it has to be kept in mind that many of the early studies used rate-dependent measures of responding, thus making the interpretation of decreases of responding by dopaminergic antagonists difficult. To our knowledge, it has not been tested to date whether mPFC ICSS can be established in animals bearing 6-OHDA lesions of the mPFC, i.e. whether the rewarding effects of mPFC ICSS involve stimulation-induced DA release within the mPFC. A similar experiment involving the sulcal prefrontal cortex, however, has been performed by Clavier and Gerfen (1981) who showed 6-OHDA lesions of this region only transiently and mildly disrupted ICSS at the same site. On the other hand, microinjections of kainic or ibotenic acid at the tip of the electrode supporting mPFC ICSS almost completely abolished self-stimulation behavior (Ferrer et al., 1985; Nassif et al., 1985). Thus, taken together, the available evidence appears to suggest that the primary effect of electrical mPFC stimulation is the activation of (direct or indirect) glutamatergic input to the VTA, which in turn increases subcortical DA release (Fiorino et al., 1993; Taber et al., 1995; Tzschentke et al., 1997; Rossetti et al., 1998; You et al., 1998). An explanation for the partly inconsistent findings concerning the role of DA in mPFC ICSS might be found in the anatomical organization of the mPFCVTA-NAS circuit. As mentioned previously, the majority of glutamatergic afferents to the VTA have been shown to synapse on non-dopaminergic cells (i.e. presumably GABAergic neurons) in the VTA (Sesack and Pickel, 1992). Given that a GABAergic projection from the VTA to the NAS/striatum also exists (van Bockstaele and Pickel, 1995) which terminates predominately on cholinergic interneurons (Pickel and Chan, 1990), it might be that the glutamatergic prefrontal cortical input to the VTA terminates predominantly not on GABAergic interneurons that would in turn inhibit dopaminergic neurons but rather on those GABAergic
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cells that project to subcortical targets. Thus, glutamatergic input to the VTA would lead to inhibition of the cholinergic interneurons in NAS/striatum, thereby decreasing excitatory cholinergic input to medium spiny neurons. This sequence of events would ultimately have the same (inhibitory) effects on NAS output neurons as DA released from the ‘direct’ dopaminergic input via a mPFC-VTA-NAS pathway. If this ‘indirect’ pathway outlined above was more important for the rewarding effects of mPFC ICSS than the ‘direct’ pathway, this would explain why the rewarding effects of mPFC ICSS appear to be mediated via glutamatergic transmission in the VTA yet seem to be relatively independent of dopaminergic mechanisms. This would mean, however, that the observed blockade of both DA release in the NAS and self-stimulation behavior by infusion of the glutamate antagonist kynurenic acid into the VTA (Tzschentke et al., 1997; You et al., 1998) are not causally related. According to this view, kynurenic acid in the VTA would block the rewarding effects of mPFC ICSS not because it blocks activation of mesoaccumbal DA neurons but rather because it blocks activation of mesoaccumbal GABA projections. The dichotomy between prefrontal cortical and subcortical DA with respect to reward is also exemplified by the findings of Duvauchelle et al. (1998). In this study it was shown that injections of the D1 antagonist SCH 23390 into the NAS increased reward thresholds (i.e. reduced the rewarding effects) of electrical VTA stimulation while injection of the same dose of SCH 23390 into the mPFC actually lowered reward thresholds (i.e. increased the rewarding effects) of the stimulation. Consistent with the latter finding, injection of the D2 antagonist flupenthixol into the mPFC also enhanced the rewarding effects of electrical VTA stimulation as measured with the place preference conditioning paradigm (Duvauchelle et al., 1992). In line with these findings is also the fact that DA agonists infused into the NAS enhance while DA agonists infused into the mPFC attenuate the rewarding effects of medial forebrain bundle ICSS (Olds, 1990). All these findings suggest that, as in the case of locomotion (see section 3.2), DA in the mPFC acts to oppose or to dampen the effects of DA in the NAS. The anatomical substrates mediating the rewarding effects of mPFC stimulation are not entirely clear. In particular, there is some debate about the extent to which ICSS produced at different sites (e.g. mPFC, VTA, MFB) are mediated by common anatomical circuits. There is considerable evidence that the primary substrate of ICSS in mPFC and MFB (i.e. the fibers/ cells that are directly activated by the stimulation) have different electrophysiological properties (Gallistel et al., 1981; Schenk and Shizgal, 1982, 1985; Schenk et al., 1985), and the different behavioral response characteristics for stimulation of the two sites (Douglin and
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Glassman, 1979; Corbett et al., 1982a, 1985; Corbett and Stellar, 1983; McGregor, 1992) also suggests that different substrates are involved. Furthermore, mPFC ICSS is not affected by lesions of the MFB, the NAS and the MD thalamus (Corbett et al., 1982b), and vice versa, even large ablations of the frontal cortex had no or only marginal effects on MFB ICSS (Stellar et al., 1982; Colle and Wise, 1987). On the other hand, the rewarding effects of ICSS in mPFC and MFB summate, at least in part (Schenk and Shizgal, 1982; Conover and Shizgal, 1992; see also Trzcinska and Bielajew, 1998), and immunohistochemical studies have detected some degree of overlap of regions expressing Fos after mPFC and MFB (self-)stimulation (see Arvanitogiannis et al., 1996, 1997a,b, 2000; Flores et al., 1997; Hunt and McGregor, 1998). However, rather surprisingly in the light of the proposed role for DA in mPFC and MFB ICSS (see above), only little Fos-expression was found in dopaminergic VTA cells after self-stimulation of both structures (Hunt and McGregor, 1998; Arvanitogiannis et al., 2000). A striking feature of mPFC ICSS, as compared to MFB or VTA ICSS, is the very slow rate of acquisition. While rats implanted with electrodes into the MFB or VTA commonly acquire lever-press behavior within a few training sessions (sometimes even within one training session of a few minutes), it may take a few weeks to establish reliable lever-pressing in rats with electrodes implanted into the mPFC, and often a considerable amount of shaping is required to establish the behavior at all (Douglin and Glassman, 1979; Corbett et al., 1985; Robertson, 1989; Mora and Cobo, 1990; McGregor, 1992). The reason for these particular properties of mPFC ICSS may relate to one or more of the following possibilities: (1) As outlined in section 3.4, the mPFC is likely to be involved in processes of behavioral inhibition. Notably, it has been observed that stimulation of the mPFC during initial training sessions inhibits ongoing behavior, in other words, lever-pressing suppresses the further expression of this very behavior (Corbett et al., 1985; McGregor, 1992). It has also been observed that acquisition speed was negatively correlated to the degree of motor inhibition caused by initial stimulation (Spence et al., 1985; McGregor, 1992). Furthermore, non-contingent stimulation of the mPFC can inhibit bar pressing for food, and open field and running wheel activity (Wilcott, 1981; Corbett and Stellar, 1983; Spence et al., 1985). Thus, it is conceivable that acquisition of mPFC ICSS proceeds in parallel to a tolerance towards the inhibitory effects of the stimulation. This is consistent with the observation that prior, pre-training non-contingent stimulation of the mPFC facilitates subsequent acquisition of lever-press behavior (Corbett et al., 1982a). However, this latter observation could also be interpreted in terms of two further possible explanations for the slow acquisition of
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mPFC ICSS. (2) There is also evidence that the mPFC is involved in emotional processes, and McGregor (1992) has found that the rate of acquisition of mPFC ICSS is negatively correlated to the aversive effects of initial stimulation (in terms of defaecation). Furthermore, it has been found that in stimulation-naive rats non-contingent stimulation of the mPFC produced a conditioned place aversion while in stimulation-experienced rats this aversion was no longer present (unpublished results, cited in McGregor, 1992). Thus, it may be that acquisition of mPFC ICSS is determined by the degree of tolerance to the aversive effects of the stimulation. (3) The observation that non-contingent prestimulation facilitates subsequent acquisition of self-stimulation can also be interpreted in yet another way. It may be that initially the stimulation only produces very weak, if any, rewarding effects, and that only with repeated and prolonged stimulation the rewarding effects of the stimulation sensitize to a degree that self-stimulation behavior is initiated and sustained. However, Corbett et al. (1985) found gradual increases in rate of lever-pressing but no evidence for a concurrent increase in rewarding effects of the stimulation (in terms of frequency thresholds) during prolonged training. (4) Finally, Fuster (1980) has shown that stimulation of the prefrontal cortex can disrupt the learning of delayed alternation and delayed response tasks. Thus, it is conceivable that the eventual acquisition of an instrumental response requires a progressive tolerance to these learning-disrupting effects during pre-training stimulation or training. In fact, Corbett et al. (1985) showed that if an instrumentally less complex response such as nose poking is required for self-stimulation, the acquisition of the response is facilitated. Of course, these above-mentioned possibilities are by no means mutually exclusive. It may be that the behavioral inhibition caused by the stimulation is experienced as aversive, or, vice versa, that the aversive stimulation effects inhibit ongoing activity. Also, it may be very difficult, experimentally and semantically, to see whether the increase in lever-pressing is due to a tolerance towards the aversive effects, thereby progressively ‘unmasking’ the rewarding effects of the stimulation, or whether the sensitization of the rewarding effects of the stimulation with a concurrent progressive ‘masking’ of the aversive effects is the primary cause for the increase in leverpressing. The picture that emerges from the available (but rather limited) literature suggests that all 4 of the above-mentioned mechanisms may contribute to the slow emergence of lever-pressing for mPFC ICSS, although several findings from the elegant study of Corbett et al. (1985) who have examined most of the alternatives outlined above suggest that the reward sensitization explanation may not be valid. However, there are still questions in this field that remain unanswered, but unfortunately, to our knowledge, there
have been no more publications addressing these issues for almost a decade. Finally, ICSS of the mPFC also provides further evidence for the notion that the mPFC is differentially involved in the mediation of the rewarding effects of drugs and that the integrity of this structure may be more important for the effects of some drugs (in particular cocaine) than for others (in particular amphetamine). Thus, while the rewarding effects of MFB self-stimulation are enhanced by various drugs of abuse (see Wise, 1996b, for review), the reward value of mPFC self-stimulation is only enhanced by cocaine and MK-801 but not by amphetamine or morphine (Spence et al., 1985; Corbett, 1989, 1991, 1992; Moody and Frank, 1990; McGregor et al., 1992).
3.1.4. Addiction and cra6ing There is evidence that the mPFC is involved not only in the mediation of the primary rewarding effects of drugs but also in neural mechanisms underlying addiction and craving. Recently, it has been demonstrated that the mPFC is actively involved in aspects of addictive behavior. Functional imaging studies in humans have shown that the mPFC is strongly activated by cocaine itself (Breiter et al., 1996), during cocaine withdrawal (Volkow et al., 1991, 1996) and, most interestingly, during cue-induced craving (Childress et al., 1996, 1999; Grant et al., 1996; Maas et al., 1998). Also, the prelimbic mPFC was among those brain sites that showed the strongest Fos expression induced by beer craving in the rat (Topple et al., 1998). Interesting evidence for an involvement of the (anterior cingulate area of the) mPFC was also reported by Neisewander et al. (2000). These authors found that exposure to a cocaine self-administration environment enhanced Fos expression in the mPFC, basolateral amygdala, NAS and some other brain areas, suggesting that this pattern of Fos expression is related to the conditioned (reinforcing) effects of cocaine. Priming injections of cocaine enhanced Fos expression in the VTA, striatum, lateral amygdala and some other brain areas. There was no difference between a group that had never received cocaine before, a group that had been self-administering cocaine and underwent extinction subsequently, and a group that had been self-administering cocaine and did not undergo extinction subsequently. This suggests that the observed pattern of Fos expression reflects the primary, unconditioned effects of cocaine. Interestingly, the anterior cingulate mPFC was the only area that showed Fos expression in response to a priming injection of cocaine only in the cocaine-experienced groups but not in the group that had never experienced cocaine before. This suggests that the enhanced Fos expression in this area reflects an experience-dependent (motivational) effect of the priming injections. Thus, in this study the anterior cingulate mPFC appeared to be the
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only area that responded to conditioned cocaine effects and showed an experience-dependent response to unconditioned cocaine effects. Dopaminergic activity is reduced in the mPFC (while it is increased in the NAS) of rats predisposed to rapid acquisition of amphetamine IV self-administration (Piazza et al., 1991; Piazza and Le Moal, 1996). This finding is consistent with the observation of Schenk et al. (1991) that reduction of dopaminergic tone in the mPFC by 6-OHDA lesions facilitates acquisition of cocaine IV self-administration. The role of the mPFC in behavioral inhibition may also be related to the presumed role of the mPFC in drug addiction. As will be outlined in section 3.3 repeated intake of drugs of abuse can alter mPFC function. Jentsch and Taylor (1999) have elaborated in a recent review that chronic drug (ab)use may result in prefrontal cortical cognitive deficits such that inappropriate unconditioned or conditioned responses to drugs, drug-related stimuli or internal drives can no longer be inhibited. From this results an excessive control over behavior by drugs or drug cues that results in craving and compulsive drug-seeking and drug-taking that cannot be suppressed or controlled by the addicted individual. Such loss of inhibitory control or increased ‘impulsivity’ can also be observed in other cases where prefrontal cortical function is disrupted, in particular in situations where it is required to shift behavioral responses away from one set of rules that have determined responding before to a new set of rules that determine responding in a different way (‘rule set shifting’). Such deficits manifest themselves as increased perseveration in go/ no go and discrimination reversal learning tasks (Iversen and Mishkin, 1970; Rosenkilde, 1979; Milner, 1982; Robbins, 1990, 1996; Damasio, 1996; Dias et al., 1996a,b, 1997). Also, lesions of the mPFC in rats and monkeys impair the extinction of an operant response (Butter, 1968; Rosenkilde, 1979; Weissenborn et al., 1997) which can also be interpreted in terms of increased perseveration. In fact, cognitive decision-making and attention processes can be altered in chronic drug abusers (O’Malley et al., 1992; Rosselli and Ardila, 1996; McKetin and Mattick, 1998; Jentsch and Roth, 1999; Rogers et al., 1999). As outlined in section 3.3, repeated administration of drugs of abuse often causes a ‘tolerance’ to the DA-releasing effects of the drug in the mPFC. If prefrontal cortical DA is a crucial element in the mediation of behavioral inhibition by the mPFC, then it is obvious how repeated intake of drugs of abuse could lead to loss of inhibitory control. Jentsch and colleagues (Jentsch et al., 1997a,b, 1998b,c,d, 1999) have shown that long-term exposure to PCP also causes a hypodopaminergic state in the prefrontal cortex. Interestingly, in these studies a good correlation was found between the degree of DA hypofunction and the degree of
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cognitive impairment (in terms of perseverative behavior and response inhibition deficits). Taken together, these observations suggest that by virtue of its role in behavioral inhibition, disturbances in mPFC function may not only be involved in psychiatric diseases but may also be an important factor in the etiology of drug abuse and addiction. It has been shown that spontaneous or precipitated withdrawal from several drugs of abuse after chronic administration causes a decrease in basal extracellular levels of DA in the NAS (Acquas et al., 1991; Parsons et al., 1991; Pothos et al., 1991; Robertson et al., 1991; Acquas and Di Chiara, 1992; Imperato et al., 1992a; Rossetti et al., 1992; Weiss et al., 1992; Crippens and Robinson, 1994; Spanagel et al., 1994; Hildebrand et al., 1998). In contrast to this, spontaneous and naloxone-precipitated withdrawal from morphine produced clear increases in extracellular levels of DA in the mPFC (Bassareo et al., 1995) while mecamylamine-induced withdrawal from chronic nicotine treatment did not significantly affect DA in the mPFC (Hildebrand et al., 1998). Unfortunately, to our knowledge only little further information exists concerning the effects of withdrawal from other drugs of abuse on DA in the mPFC. Dworkin and Smith (1992) reported that 24 h of withdrawal from self-administered cocaine had no effect on DA turnover rate in the frontal cortex but decreased serotonin turnover in this brain region. It is, however, difficult to compare these data to those of Bassareo et al. (1995) since the data from the self-administering animals was compared to that of yoked controls. Thus, these data would show differential effects of withdrawal from contingent versus non-contingent cocaine but not effects of withdrawal from cocaine as such. Nevertheless, the finding for morphine suggests that mesoaccumbal and mesocortical dopaminergic neurons are affected in an opposite way during withdrawal. Since withdrawal from a chronically administered drug of abuse certainly is experienced as a stressful situation, this increase in extracellular DA levels in the mPFC is consistent with the high responsiveness of the mesocortical projection to stress (see section 2.2.2).
3.2. Motor beha6ior 3.2.1. Effects of intra-mPFC drug injections Amphetamine injections into the mPFC were found to reduce hyperlocomotion induced by intra-NAS injections of amphetamine without producing an effect on locomotion by itself (Vezina et al., 1991; Hooks et al., 1992; Tassin et al., 1992). However, intra-mPFC injections of amphetamine were also reported to produce moderate increases in open-field activity, although the effects were much weaker compared to those obtained by injection of amphetamine into the NAS (Dougherty
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and Ellinwood, 1981; Carr and White, 1987; Kelley et al., 1989). Intra-mPFC injection of the D1 receptor antagonist SCH23390 (but not of the D2 receptor antagonist sulpiride) increased the locomotor-stimulatory effect of intra-NAS amphetamine while having no effect on locomotion by itself (Vezina et al., 1991, 1994; it should be mentioned here, however, that 2 days following the initial injections animals in the latter study actually showed an attenuated response to intraNAS injection of amphetamine, suggesting that even short-term D1 receptor blockade in the mPFC can have lasting effects on subcortical dopaminergic neurotransmission). Conversely, catalepsy induced by peripheral administration of haloperidol was potentiated by intramPFC injection of apomorphine which, by itself, had no effect on catalepsy scores (Bubser and Schmidt, 1994). Very surprisingly, Tucci et al. (1994) reported that intra-mPFC injections of DA clearly reduced the catalepsy produced by systemically administered haloperidol, a finding which is clearly incompatible with most other results. Apomorphine or amphetamine injections into the mPFC were also found to decrease spontaneous and amphetamine-induced open-field activity (Broersen et al., 1999; Lacroix et al., 2000). Injection of the specific DA reuptake inhibitor GBR 12909 into the mPFC also reduced novelty-induced locomotor activity, an effect that was attenuated by co-injection of a D1 or a D2 receptor antagonist, suggesting that the inhibitory effects of increased mPFC DA levels were mediated via both receptor subtypes (Radcliffe and Erwin, 1996). On the other hand, injection of the D2 receptor antagonist cis-flupenthixol into the mPFC failed affect the locomotor response to systemic amphetamine (Lacroix et al., 2000). Further evidence for the ‘inverse’ relationship of mPFC DA transmission and locomotor activity was presented recently by Hedou et al. (1999) who found a significant negative correlation between DA levels in the mPFC and locomotor activity (but a significant positive correlation between DA in the NAS and locomotor activity) after systemic administration of cocaine. Vice versa, locomotor hyperactivity was found to be positively correlated to the degree of DA depletion in the mPFC induced by lesioning the VTA or dopaminergic afferents of the mPFC (Tassin et al., 1978b). However, conflicting results come from a report by Klockgether et al. (1988) who found that intra-mPFC injection of the DA antagonist haloperidol produced catalepsy (much like intra-NAS or intrastriatal injections of haloperidol also produce catalepsy (Ellenbroek et al., 1985; Meyer et al., 1993)) and from a series of studies by Beninger and collegues on the effects of intra-mPFC injections of DA agonist and antagonist drugs on circling behavior (Morency et al., 1985, 1987; Stewart et al., 1985; Beninger et al., 1990). Based on their results these authors concluded that prefrontal
cortical DA, via a predominant action on D2 receptors, exerts a stimulatory influence on locomotor behavior. It is difficult to explain these findings along the same lines as the findings for excitotoxic lesions of the mPFC (see below) since alterations in postsynaptic DA receptor functions seem very unlikely given the fact that drugs were injected acutely into the mPFC. The reason for these discrepant findings remains unclear. Evidence for a role of the mPFC in the conditioned locomotor effects of amphetamine was presented by Mead et al. (1999) who found that pairing of a specific environment and amphetamine resulted in subsequent conditioned locomotion and c-fos expression in the mPFC upon exposure to that environment without prior drug administration. The AMPA/kainate receptor antagonist NBQX blocked the expression of the conditioned activity as well as the increase in mPFC c-fos expression, suggesting that AMPA receptors in the mPFC may participate in the mediation of amphetamine’s conditioned locomotor effects. Finally, Ikemoto and Goeders (2000) have shown that intra-mPFC injection of the muscarinic cholinergic antagonist scopolamine increased locomotor activity. However, such injections also attenuated the locomotor activity induced by systemic administration of cocaine, suggesting a rather complex role for cholinergic regulation of spontaneous and drug-induced locomotor activity.
3.2.2. Effects of mPFC lesions 3.2.2.1. 6 -OHDA lesions. In contrast to DA depletions in the NAS, the effects of DA depletions in the mPFC on motor behavior have been somewhat inconsistent. It has been shown early on and many times subsequently that 6-OHDA lesions of the NAS attenuate the behavioral effects of amphetamine and other indirect DA agonists (Kelly et al., 1975; Joyce et al., 1983), produce at least a transient decrease in spontaneous activity (Joyce et al., 1983) but increase the effects of direct DA agonists (Kelly et al., 1975; Joyce et al., 1983) presumably by inducing denervation supersensitivity of postsynaptic DA receptors in the NAS. The findings for 6-OHDA lesions in the mPFC on locomotor activity have been more variable. No effects on spontaneous and/or DA agonist-induced activity (Joyce et al., 1983; Oades et al., 1986; Clarke et al., 1988; Hemby et al., 1992b; Burns et al., 1993; Banks and Gratton, 1995), reduced spontaneous and/or DA agonist-induced activity (Sokolowski and Salamone, 1994; King and Finlay, 1995; Espejo, 1997; King et al., 1997) and enhanced spontaneous and/or DA agonist-induced activity (Carter and Pycock, 1980; Pycock et al., 1980b; Robinson and Stitt, 1981; Joyce et al., 1983; Bubser and Schmidt, 1990; Vezina et al., 1991; Duvauchelle et al., 1992; Jones and Robbins, 1992; Beyer and Steketee,
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1999) have all been reported. Due to the particularities of the mesocortical DA projection the outcome of a 6-OHDA lesion in the mPFC may depend much more on the exact degree of DA depletion than in the NAS. In addition, noradrenergic innervation, which is also affected by 6-OHDA, is much more prominent in the mPFC than in the NAS, which may introduce an additional potential source of variation for the effects of mPFC 6-OHDA lesions. Other points to consider in this context are the apparent functional heterogeneity of the mPFC (as outlined in more detail in section 4), and the possible development of denervation supersensitivity. Such effects have long been described for the striatum/NAS by the pioneers of this technique (Ungerstedt, 1971), and evidence exists that similar phenomena also occur in the mPFC (Haroutunian et al., 1988; Shibata et al., 1990, 1992).
3.2.2.2. Excitotoxic lesions. A potentiation of behaviors related to enhanced dopaminergic transmission in NAS and striatum following excitotoxic lesions of the mPFC has been reported. In early studies it was shown that relatively large excitotoxic or ablative lesions of the mPFC produce spontaneous locomotor hyperactivity (Richter and Hawkes, 1939; Lynch, 1970; Kolb, 1974a,b,c). Animals bearing more restricted ibotenic acid lesions of the mPFC showed attenuated haloperidol-induced catalepsy and enhanced apomorphine-induced stereotypy (Scatton et al., 1982; Worms et al., 1985; Braun et al., 1993; Jaskiw et al., 1993; Lipska et al., 1995), enhanced amphetamine-induced hyperactivity (Jaskiw et al., 1990a), (at least transiently) elevated levels of basal activity (Jaskiw et al., 1990a; Yee, 2000), and enhanced response to stress (Jaskiw et al., 1990b; Jaskiw and Weinberger, 1992). Consistent with these observations is the finding that TTX infusion into the mPFC (which would block the activity of corticofugal projections) also leads to an enhancement of dopaminergic transmission in the NAS (Louilot et al., 1989). However, as in the case of 6-OHDA lesions the findings for the effects of excitotoxic lesions on motor activity are not entirely consistent. Weissenborn et al. (1997) reported that quinolinic acid lesions of the mPFC enhanced locomotor activity in a novel environment but did not affect the locomotor-stimulant effects of cocaine. Likewise, Lacroix et al. (1998) found that NMDA lesions of the mPFC increased spontaneous activity in an open field but did not significantly affect the locomotor response to amphetamine. Wolf and Xue (1999) also reported that ibotenic acid lesions of the mPFC did not affect amphetamine-induced locomotor activity. Finally, Tzschentke and Schmidt (1999, 2000a) found no effects of small or large mPFC quinolinic acid lesions on spontaneous activity and on cocaine- and amphetamine-induced locomotor activity. In the study by Isaac et al. (1989) aspiration lesions of the mPFC
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did not affect spontaneous activity in the open field or in the running wheel. If one assumes that DA in the mPFC inhibits pyramidal cells and that glutamatergic corticofugal projections to the VTA (and/or to the PPTg) activate dopaminergic cells (see sections 2.3.1 and 2.3.2) it is surprising that excitotoxic and 6-OHDA lesions of the mPFC should have essentially the same effects on behaviors related to subcortical dopaminergic activity. While the explanation for the effects of 6-OHDA lesions, based on the above assumptions, is quite straightforward (removal of the inhibitory dopaminergic tone in the mPFC would ‘disinhibit’ glutamatergic excitatory projections to the VTA), the explanation for the effects of excitotoxic lesions is less clear. At first sight one would expect that the removal of the excitatory mPFC output to the VTA leads to a decrease in behaviors related to dopaminergic activity. The findings with apomorphine in particular, however, suggest that the observed effects (i.e. increase in behaviors related to dopaminergic activity) are due to alterations in postsynaptic DA receptors in the NAS/striatum. The removal of excitatory input to the VTA could initially lead to decreased DA input to subcortical sites which could then produce a ‘secondary’ denervation supersensitivity of DA receptors in postsynaptic NAS/striatum neurons. The observation that mPFC lesions increase spontaneous behavior might be related to the fact that mPFC lesions have also been shown to slow habituation to new situations or environments (Glaser and Griffin, 1962; Kolb, 1974c). Since in most studies examining spontaneous activity animals were transferred from their home cages to a presumably relatively novel test environment it is conceivable that reduced habituation can result in elevated levels of activity. Another aspect that should be kept in mind when discussing the effects of mPFC lesions on spontaneous activity is that impairing mPFC function may increase behavioral measures of anxiety or timidity, such as thigmotaxis in an open field or time spent on the closed arms of an elevated plus maze (Nonneman et al., 1974; Holson, 1986a,b; Jaskiw and Weinberger, 1990; Morgan and LeDoux, 1995; Jinks and McGregor, 1997). Thus, in particular, when locomotor activity of lesioned animals is tested under stressful conditions (e.g. in a novel environment or in large open fields), these anxiety or timidity effects may influence the expression of spontaneous behavior. If a reduction of such behavior is observed in mPFC-lesioned animals the possibility should be considered that this effect may not be a ‘genuine’ reduction in locomotor activity but may be the expression of anxiety-induced suppression of ongoing behavior.
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3.3. Beha6ioral sensitization The mPFC is not only involved in the mediation of the acute effects of drugs but also in the mediation of the long-term consequences of repeated drug administration on neurochemistry and behavior. Although it remains to be determined whether the mPFC plays a role in the development of tolerance to drugs, there is good evidence that the mPFC is involved in at least some forms of sensitization and that the repeated administration of drugs can lead to changes in prefrontal cortical neurotransmission. The term ‘behavioral sensitization’ refers to the progressive increase in the behavioral response (in most cases measured as locomotion or stereotypic behaviors) to the repeated administration of a constant drug dose. The interest in the mPFC in the context of sensitization has increased because of the suggestion that glutamatergic inputs to the VTA are an essential element in the circuitry mediating the initiation of sensitization (Sorg and Kalivas, 1993b; Perugini and Vezina, 1994; Cador et al., 1995; Kalivas, 1995, for details about the circuitry and mechanisms thought to be involved in sensitization). Evidence for a possible causal relationship between drug-induced release of glutamate in the VTA and sensitization, and the importance of the mPFC as a source of glutamate in the VTA, was provided by Wolf and Xue (1999) who showed that those treatments that have been shown to block the development of amphetamine sensitization also block the amphetamine-induced increase in VTA glutamate release (i.e. treatment with MK-801 or SCH23390 (Wolf and Xue, 1999), excitotoxic lesions of the mPFC (see Wolf, 1998; but see discussion below for conflicting findings concerning mPFC lesion effects on the development and expression of sensitization)). Also, D1 receptors are located on the terminals of glutamatergic fibers originating from the mPFC (Dewar et al., 1997; Lu et al., 1997b), although the relation of activation of these presynaptic D1 receptors and the increase in extracellular glutamate may not be trivial since in other brain areas such presynaptic D1 receptors have been shown to have inhibitory rather than facilitatory effects on transmitter release and neuronal excitation (Pennartz et al., 1992; Momiyama et al., 1996; Nicola et al., 1996; Nicola and Malenka, 1997). In addition, presynaptic D1 receptors in the VTA are also located on GABAergic terminals where they facilitate GABA release (Cameron and Williams, 1993). Thus, the mechanisms at the level of the VTA involved in the initiation of sensitization may be more complex than a ‘simple’ feed-forward loop between symatodendritic DA and D1 receptors on glutamatergic terminals.
3.3.1. Alterations in DA release during repeated drug administration A single administration of amphetamine has been shown to induce persistent, time-dependent behavioral as well as neurochemical sensitization. Interestingly, while the effects of a challenge injection of amphetamine on locomotion and DA release in the NAS became progressively stronger with increasing withdrawal duration, the effects on mPFC DA release decreased with prolonged withdrawal (Vanderschuren et al., 1999). This is consistent with the notion that prefrontal DA functionally antagonizes the effects of psychostimulants and other drugs on locomotion and NAS DA release (Louilot et al., 1989; Vezina et al., 1991; see discussion in section 3.2) such that a tolerance to the drug effect in the mPFC might contribute to the emergence of sensitization to the drug effect on DA release in the NAS and on the behavioral level (Banks and Gratton, 1995; Prasad et al., 1999). Long-term treatment with cocaine was also reported to induce a longlasting (\ 6 weeks) decrease in basal DA turnover in the mPFC but not in the NAS and striatum, where the reduction in DA turnover was only a transient effect (B 1 week) (Karoum et al., 1990). The potential importance of ‘tolerance’ to the DA-releasing effects of drugs in the mPFC for the emergence (i.e. ‘disinhibition’) of sensitization is also suggested by several other findings. As outlined in previous sections, stress can induce a clear DA release in the mPFC. This stress-induced mPFC DA release is strongly reduced in animals sensitized to cocaine, suggesting that a sensitizing drug treatment ‘blunts’ the DA response in the mPFC not only to the drug itself but also to other challenges (Sorg and Kalivas, 1993a,b). The reverse was also found, i.e. animals that had experienced repeated footshock stress did not show a sensitized DA release in the mPFC in response to an acute cocaine challenge (although they did show a sensitized DA response in the NAS) (Sorg, 1992). The observed tolerance to cocaine’s DA-releasing effects in the mPFC was not due to altered releasability of DA from mesocortical terminals nor to altered response of prefrontal cortical DA terminals to the local effects of cocaine (Sorg et al., 1997). A tolerance to the DA-releasing effects of morphine in the mPFC (with a concurrent increase in DA release in the NAS) with repeated, sensitizing treatment has also been reported (Tassin et al., 1992; Vezina et al., 1992), and a similar decrease of effect of repeated treatment with ketamine or PCP on extracellular levels of mPFC DA (with a concurrent increase in basal DA levels in the mPFC) was found as well (Jentsch et al., 1997a,b, 1998b; Lindefors et al., 1997). Furthermore, a similar effect (i.e. tolerance to the DA-releasing effects in the mPFC) was found for repeated administration of delta-9-tetrahydrocannabinol (THC) (Jentsch et al.,
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1998a). Finally, a tolerance to the effects of amphetamine on the mPFC with repeated treatment was observed not only with respect to DA transmission (see above) but also with respect to c-fos expression in the mPFC induced by amphetamine, although the latter effect may well be a consequence of the former effect, since co-treatment with a D4 receptor antagonist blocked the induction of c-fos expression by acute amphetamine treatment (Feldpausch et al., 1998). Interestingly, White et al. (1995a) presented evidence that with repeated cocaine administration the inhibitory response of pyramidal cells to DA also decreased, i.e. the decrease of inhibitory effects of DA on mPFC efferents in the course of sensitization may be related not only to a reduction in the amount of DA released but also to a reduced capacity of the released DA to induce inhibition of postsynaptic cells. It should be noted, however, that this ‘blunting’ or ‘disinhibition’ may not be a universal mechanism responsible for the development of sensitization to all drugs that have been found to induce behavioral sensitization. For example, a rather opposite effect has been found in the course of the development of nicotine sensitization, i.e. no effect or even a reduction in subcortical dopaminergic activity but an increase in prefrontal cortical DA utilization and release, and an increase in prefrontal cortical Fos expression by repeated, sensitizing treatment with nicotine (Vezina et al., 1992; Nisell et al., 1996, 1997). Others have shown that amphetamine sensitization can be associated with a sensitized DA response in both structures (Robinson et al., 1988; Stephans and Yamamoto, 1995). As mentioned above, a tolerance to the DA-releasing effects in the mPFC of a cocaine-challenge in stress-preexposed animals and also the reverse, i.e. a tolerance to the DA-releasing effects in the mPFC of an acute exposure to stress in cocaine-pretreated animals has been found (Sorg and Kalivas, 1993a). On the other hand, Hamamura and Fibiger (1993) reported that exposing amphetamine-sensitized rats to stress did produce a sensitized DA response in the mPFC, although the mPFC DA response to an amphetamine challenge was not different in sensitized and control animals. This would suggest that prefrontal DA is involved in crosssensitization between amphetamine and stress but not in amphetamine-induced sensitization as such. Furthermore, in animals sensitized by repeated injections of methamphetamine, potassium-evoked release of DA in the mPFC (but not in the striatum) was enhanced compared to control animals, and methamphetamineinduced DA release in the mPFC (but not in the striatum) was also greater in methamphetamine-pretreated animals (Stephans and Yamamoto, 1995). The finding of Sorg et al. (1997) that intra-cortical administration of cocaine did not mimic the effect of systemically administered cocaine in sensitized animals
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(i.e. unlike systemic cocaine, locally applied cocaine still produced a sensitized DA response within the mPFC) suggests that this tolerance is not due to local changes within the mPFC but rather due to changes in the regulation of mesocortical neurons at the level of the VTA. To our knowledge, it has not been systematically examined yet whether mesocortical DA neurons in cocaine- or morphine- versus amphetamine- or nicotine-sensitized animals would respond differentially to synaptic inputs at the level of the VTA or whether these synaptic inputs (i.e. afferent regulation of the VTA; see Kalivas, 1993) themselves would be differentially altered in cocaine- or morphine- versus amphetamine- or nicotine-sensitized animals. As in the case of psychomotor stimulants, chronic administration of neuroleptic drugs has also been shown to cause differential alterations in dopaminergic activity in mPFC and NAS/striatum. Thus, acute administration of a neuroleptic drug increases dopaminergic activity (synthesis, metabolism, release) in both mPFC and NAS/striatum (Carlsson and Lindqvist, 1963; Scatton et al., 1976; Scatton, 1977; Matsumoto et al., 1983; Moghaddam and Bunney, 1990). However, chronic treatment is associated with an attenuation (i.e. tolerance) of this increase in dopaminergic activity in the NAS/striatum but not or only to a much lesser degree in the mPFC (Scatton et al., 1976; Scatton, 1977; Bacopoulos et al., 1978, 1979, 1980, 1982; Nicolaou, 1980; Bannon et al., 1982, 1983; Bowers and Hoffman, 1986; Moghaddam and Bunney, 1990; but see Chang et al., 1989; Essig and Kilpatrick, 1991). An alternative way to interpret these data is to acknowledge that repeated neuroleptic administration can result in depolarization inactivation in midbrain dopaminergic neurons (Bunney and Grace, 1978; Chiodo and Bunney, 1983; White and Wang, 1983). Interestingly, Chiodo and Bunney (1983) found that after induction of depolarization inactivation in most VTA neurons, the majority of neurons that were still active projected to the mPFC. Thus, the apparent tolerance to the stimulatory effects of neuroleptics on dopaminergic activity in the NAS/striatum may be due to the emergence of depolarization inactivation with prolonged treatment, and the observed lack of tolerance to these effects in the mPFC may be related to the fact that mesocortical DA neurons are not driven into depolarization inactivation to the same degree by the neuroleptic treatment. In summary, the role of the mPFC in sensitization mechanisms, as established so far, is presumed to be twofold. Firstly, prefrontal cortical efferents to the VTA are thought to provide important glutamatergic input to DA neurons, which, acting via NMDA receptors, provides a crucial signal for the initiation of sensitization. The tolerance to the DA-releasing effects in the mPFC of at least certain sensitizing drugs that develops with repeated treatment might be one mecha-
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nism which enhances the glutamatergic signal in the VTA over time by reducing dopaminergic inhibition of mPFC pyramidal cells projecting to the VTA. Thus, via its projections to the VTA the mPFC is thought to be involved in the initiation of sensitization. Secondly, prefrontal cortical efferents to the NAS are thought to provide important glutamatergic input to spiny neurons, which, acting via AMPA receptors, provides a crucial signal for the expression of sensitization. The enhanced glutamatergic transmission in the NAS might also be due to reduced dopaminergic inhibition within the mPFC. A more detailed consideration of the mechanisms thought to underlie the development and expression of sensitization is beyond the scope of this review, but the reader is referred to a number of several further reviews that cover this topic in detail (Kalivas and Stewart, 1991; Sorg and Kalivas, 1993b; Wise and Leeb, 1993; Kalivas, 1995; White, 1996; Pierce and Kalivas, 1997; Wolf, 1998).
3.3.2. Lesion effects Studies using excitotoxic lesions of the mPFC have produced conflicting findings on the role of the mPFC in the development and expression of sensitization induced by amphetamine and cocaine. For amphetamineinduced sensitization it was reported that ibotenic acid lesions of the mPFC blocked the development of locomotor sensitization induced by repeated low dose systemic or intra-VTA administration of amphetamine (Cador et al., 1999) and also the development of sensitization of post-stereotypy hyperlocomotion (but not sensitization of stereotypy itself) induced by repeated systemic administration of high doses of amphetamine (Wolf et al., 1995). On the other hand, no effect of quinolinic acid lesions of the mPFC on the development of amphetamine-induced sensitization has also been reported (Tzschentke and Schmidt, 1998a,b), and the expression of amphetamine sensitization was found to be unaffected by ibotenic acid lesions when lesions were made after sensitization was established (Li and Wolf, 1997). The reported lack of effect of mPFC lesions on amphetamine-induced sensitization is compatible with the findings of Clarke et al. (1988) who showed that 6-OHDA lesions of the NAS but not of the mPFC reduced the acute locomotor response to amphetamine. This finding also argues for a relative independence of amphetamine effects from the mPFC and, in particular, of dopaminergic transmission in the mPFC. This is consistent with the observation that single or even repeated intra-mPFC infusions of amphetamine do not affect spontaneous locomotor activity and the locomotion induced by acute systemic injection of amphetamine, cocaine or caffeine (Hooks et al., 1992; Ben-Shahar and Ettenberg, 1998).
With respect to cocaine-induced sensitization the picture is equally inconsistent. While Tzschentke and Schmidt (1998c,a,b) and Li et al. (1999b) reported that the development of sensitization on the behavioral and cellular level was blocked by excitotoxic lesions of the mPFC, Weissenborn et al. (1997) found no effect of on the development of cocaine-induced sensitization. As regards the expression of cocaine-induced sensitization, no effect of mPFC lesions was found in one study (Li et al., 1999a) while lesions of the dorsal (but not of the ventral) mPFC blocked the expression of the sensitized behavioral response to cocaine in another study (Pierce et al., 1998). We have recently found that quinolinic acid lesions of the mPFC blocked the expression of morphine-induced behavioral sensitization but not the expression of sensitization induced by MK-801 (Tzschentke and Schmidt, 2000b). The reason for these discrepancies is not clear, but it may be that they are due to procedural differences since different neurotoxins, toxin infusion sites, drug doses, treatment and test protocols were used and different behavioral measures were taken in the above-mentioned studies. Interestingly, Banks and Gratton (1995) reported that 6-OHDA lesions of the mPFC while attenuating the acute response to amphetamine actually enhanced sensitization produced by subsequent repeated systemic amphetamine injections on the behavioral (i.e. locomotor activity) as well as on the neurochemical (i.e. DA release in the NAS) level. This observation is nicely complemented by the finding that intra-mPFC infusions of amphetamine together with peripheral amphetamine injections can attenuate the development of sensitization (Ben-Shahar and Ettenberg, 1998). In this case, amphetamine administered into the mPFC would ‘compensate’ for the tolerance in the DA response developing to the peripheral amphetamine administration and would keep DA concentrations at a high level during each peripheral injection of the drug (Maisonneuve et al., 1990). Interestingly, the data from this latter study suggested that intra-mPFC infusions of amphetamine blocked the ‘pharmacological’, i.e. context-independent aspects of sensitization but did not affect the ‘conditioned’, i.e. context-dependent aspects of sensitization. The inhibitory effects of prefrontal DA on sensitization processes does not seem to be specific to sensitization induced by pharmacological agents but is also seen in cases where sensitization effects are induced by repeated exposure to naturally reinforcing stimuli. Thus, Mitchell and Gratton (1992) found that partial mPFC DA depletions enhanced the development of sensitization to the NAS DA releasing effects of sexual stimuli.
3.3.3. Possible differential role of the mPFC in cocaine- 6ersus amphetamine-induced sensitization From the data reviewed in the preceding sections it is
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obvious not only that the findings concerning the role of the mPFC in reward- and sensitization-related processes in general are rather inconsistent, but also that, in particular, striking differences seem to exist with respect to the role of the mPFC between cocaine and amphetamine sensitization. The reason for these differences is not known. It is interesting to note, however, that there are a number of differences in the effects of both drugs that relate to the mPFC in one way or another. For example, it has been shown that both drugs differentially affect firing of mesocortical neurons. Thus, while both drugs inhibit firing of mesoaccumbal neurons (White et al., 1987; Einhorn et al., 1988), only amphetamine inhibits firing of mesocortical neurons while cocaine fails to do so (Wang, 1981; Chiodo et al., 1984; White et al., 1987). Furthermore, while amphetamine exerts its effects relatively selectively on dopaminergic neurons, cocaine, in addition to its blockade of the DA transporter, also has prominent direct effects on other neurons as well. Cocaine also blocks with high affinity the NA and 5-HT transporters (Reith et al., 1986, 1997). Given the complex mutual pre- and postsynaptic interactions within the mPFC between these monoamines, it may not be surprising that cocaine and amphetamine can have quite different effects with respect to mPFC function. Of particular relevance may be the fact that the NA transporter significantly contributes to the removal of DA from the synaptic cleft in the mPFC (see section 2.2.4). DA released by amphetamine could thus still be removed from the synaptic cleft by the NA transporter while this mechanisms of DA inactivation would not be available in the cocaine-treated animal due to the concurrent blockade of DA as well as NA transporters by cocaine. One basic difference between amphetamine and cocaine with respect to their effect on extracellular DA levels is that the effect of amphetamine is at least partly impulse-independent while the effect of cocaine is impulse-dependent (Benwell et al., 1993; Kuczenski and Segal, 1994). Since mesocortical DA neurons have a higher rate of impulse-flow (higher firing rate and higher rate of DA release) than other DA neurons, cocaine may be particularly potent in exerting its effects in the mPFC relative to subcortical sites while amphetamine would affect all DA neurons in a similar fashion independently of their activity level. Therefore, the mPFC might play a relatively more important role in the mediation of cocaine-induced behavioural effects, including sensitization. At the subcortical level, additional differences between cocaine and amphetamine effects after acute and, in particular, chronic administration have also been observed. Evidence that the mPFC may be more important for cocaine-induced sensitization than for amphetamine-induced sensitization comes from microdialysis studies measuring extracellular levels of
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glutamate in the NAS during a challenge with the respective sensitizing drug after a sensitization has been established. Thus, cocaine-sensitized rats release more glutamate in the NAS (core) than non-sensitized rats in response to a cocaine challenge, an effect that was blocked by ibotenic acid lesions of the dorsal mPFC (Pierce et al., 1998). In contrast, no difference was found between amphetamine-sensitized and non-sensitized rats in response to an amphetamine challenge (Xue et al., 1996). After withdrawal from chronic amphetamine treatment, a decrease in the levels of GluR1 and GluR2 receptor subunits and their respective mRNA was observed in the NAS (Lu et al., 1997a; Lu and Wolf, 1999). In contrast, no such decrease was observed after withdrawal from chronic cocaine (if anything, there was a strong trend towards an elevation of the levels of GluR1 mRNA (Ghasemzadeh et al., 1999). Furthermore, the cocaine-induced increase in extracellular glutamate levels in the NAS was augmented by repeated cocaine injections (Pierce et al., 1996; Reid and Berger, 1996) while the delayed increase in NAS glutamate levels produced by amphetamine was not altered during repeated amphetamine treatments (Xue et al., 1996). Thus, it is not only the function of the mPFC that is differentially affected by cocaine and amphetamine, but also other central structures of the mesocorticolimbic circuit. In fact, these latter findings for NAS glutamate release nicely fit into the general picture. As mentioned above, cocaine — but not amphetamine — induced DA release in the mPFC shows tolerance with repeated drug administration. If one assumes that neuronal glutamate measured in the NAS is predominantly of prefrontal cortical origin, then the observed increase in glutamate after chronic cocaine, but not amphetamine, could directly be related to the diminished dopaminergic inhibition of corticofugal pyramidal cells in the mPFC. Although this scenario is speculative, it can easily be subjected to experimental testing, and the results from such studies could potentially make a considerable contribution to our understanding of sensitization in general and of the neurobiological mechanisms underlying the differences between cocaine and amphetamine in particular. A number of other approaches have been used to examine the role of the mPFC in amphetamine and cocaine sensitization. Firstly, electrical kindling of the mPFC produced sensitization to the locomotor activating effects of cocaine (Schenk and Snow, 1994). In the light of the above-mentioned apparent differences with respect to the role of the mPFC for cocaine- and amphetamine-induced sensitization, it would be interesting to determine whether such a kindling regimen of the mPFC would also sensitize animals to the locomotor-activating effects of amphetamine. Since such an
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effect was already demonstrated for amygdala kindling (Kirkby and Kokkinidis, 1987; Gelowitz and Kokkinidis, 1993) and since repeated amphetamine administration has been shown to produce an increase of DA release in the amygdala (Harmer et al., 1997; Harmer and Phillips, 1999) it may be well worth to further explore the role of the mesoamygdaloid DA projection in amphetamine sensitization. Secondly, a behaviorally sensitizing regimen of repeated amphetamine administrations has been shown to alter the reactivity of VTA DA neurons to electrical stimulation of the mPFC, such that mPFC stimulation produced bursts in VTA DA neurons on a greater number of trials after short (i.e. 2-day) withdrawal, and that VTA DA neurons showed a greater relative percentage of purely excitatory responses compared to inhibitory/excitatory responses after mPFC stimulation after longer (i.e. 10-day) withdrawal. In other words, in amphetamine-sensitized animals electrical stimulation of the mPFC produced an overall greater stimulation of midbrain dopaminergic cells than in control rats (Tong et al., 1995; Clark and Overton, 1998). Although it is not possible to decide on the basis of these results whether the observed effects are due to enhanced responsiveness of the mPFC to the applied electrical stimulation or to enhanced responsiveness of DA neurons to a given excitatory input, it is nevertheless possible that the observed effects are due only to the latter, i.e. the effects produced by chronic amphetamine could be entirely mediated at the level of the VTA, in the absence of any alterations within the mPFC. This interpretation is supported by the observation that chronic amphetamine or cocaine administration increases the expression of the NMDA receptor subunit NMDAR1 and the AMPA receptor subunit GluR1 in the VTA (Fitzgerald et al., 1996), and that after chronic amphetamine or cocaine administration VTA DA neurons are more sensitive to iontophoretically applied glutamate, in that they more readily enter a state of apparent depolarization blockade (White et al., 1995b). It should be mentioned, however, that an increase in the expression of GluR1 subunits and a decrease in the expression of NMDAR1 subunits and their corresponding mRNA has also been observed in the mPFC following withdrawal from chronic amphetamine treatment, indicating that alterations intrinsic to the mPFC may also be involved in the chronic actions of amphetamine (Lu et al., 1997a, 1999a,b; Lu and Wolf, 1999). Unfortunately, from the results of the latter studies it is difficult to determine whether the changes in receptor subunit expression occurred in pyramidal cells or interneurons or both, although the available data suggests that, at least in the case of NMDAR1, the relevant receptors may be located on pyramidal neurons (Conti et al., 1994; Petralia et al., 1994a,b; Rudolf et al., 1996). A further complicating factor (which in
fact applies to many other sensitization experiments as well) is that the respective alterations were observed only after a period of withdrawal from repeated drug treatment. Thus, it is often not clear whether the observed adaptations were produced by the repeated drug treatment per se or by alterations induced by the withdrawal. This point is nicely demonstrated by the findings of Onn and Grace (2000) who showed, using a combination of electrophysiological and anatomical techniques, that repeated amphetamine injections can alter the electrophysiological and structural characteristics of mPFC pyramidal cells as well as of NAS spiny neurons. It was shown that after 7 or more days of withdrawal from repeated amphetamine there was an increased incidence of dye coupling in both neuron populations. Furthermore, a larger proportion of prefrontal pyramidal cells showed burst activity, and a larger proportion of both cortical pyramidal cells and NAS spiny neurons showed bistable membrane oscillations. Notably, none of these changes were observed when measurements were taken during the treatment period. Thirdly, structural changes have been observed in both the mPFC and the NAS following a sensitizing treatment with amphetamine, cocaine, or morphine (Robinson and Kolb, 1997, 1999a,b). These findings show that repeated administration of amphetamine and other drugs can induce persistent changes in the mPFC. What is not clear, however, from these data is the extent to which these alterations are of relevance for the manifestation of the observed behavioral and neurochemical effects. In other words, it is not known whether these changes are causally related to the observed effects or whether they are mere accompanying phenomena without a causal relationship to the observed behavioral and neurochemical effects. Taken together, while comprehensive evidence suggests that behavioral sensitization to amphetamine and cocaine (as well as other drugs of abuse) is closely and positively linked to an increase in DA release in the NAS/striatum (Robinson and Becker, 1986; Robinson et al., 1988; Kazahaya et al., 1989; Akimoto et al., 1990; Kalivas and Duffy, 1990; Petit et al., 1990; Hamamura et al., 1991; Patrick et al., 1991), the situation for the role of mPFC DA release is much less clear and may depend on the behavioral procedure employed and, in particular, on the type of drug used to produce sensitization. The findings reviewed in this section suggest that it would be too simple to state that the mPFC is or is not involved in sensitization processes. One clearly has to distinguish between different drugs, the sensitization to which may depend to a differential degree on mPFC function. One also has to differentiate between the role of the dopaminergic innervation of the mPFC in sensitization processes and functions of the mPFC which are not directly related to dopaminergic
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mechanisms but which may nevertheless be important for the development or expression of sensitization to different drugs.
3.4. Schizophrenia and cognition One of the most long-standing assertions about the function of the prefrontal cortex is that it is importantly involved in cognitive processes such as attention, response selection and inhibition, spatial learning, temporal sequencing of actions, planning of forthcoming behavior based on previously acquired information, and working memory. These functions have been inferred from deficits in paradigms such as delayed alternation, delayed non-matching-to-position, delayed non-matching-to-sample, reversal learning, go/no-go alternation, and various maze (Y, radial-arm, water maze) and attention tasks in experimental animals or deficits in the Wisconsin Card Sort task in humans, caused by lesions or pharmacological disruption of the prefrontal cortex (see e.g. Milner, 1963; Brozoski et al., 1979; Fuster, 1980; Simon et al., 1980; Simon, 1981; Kolb et al., 1983; Kolb, 1984; Milner and Petrides, 1984; Sakurai and Sugimoto, 1985; Doar et al., 1987; Wolf et al., 1987; Olton et al., 1988; van Haaren et al., 1988; Stam et al., 1989; Bubser and Schmidt, 1990; Goldman-Rakic, 1990; Poucet, 1990; Wilcott and Xuemei, 1990; McCarthy et al., 1994; Sokolowski and Salamone, 1994; Broersen et al., 1995; Granon et al., 1995; Seamans et al., 1995b; Murphy et al., 1996a; Muir et al., 1996; Bussey et al., 1997b; Schultz et al., 1998; Broersen and Uylings, 1999; Delatour and Gisquet-Verrier, 1999; Floresco et al., 1999; Ragozzino et al., 1999). One of the most prominent views about the overall function of the prefrontal cortex is that ‘‘… it functions to provide flexibility and unity in behavior by providing a kind of temporal structure in which behavior is organized over time into a meaningful whole’’. (Kolb, 1984, p.89; see also Fuster, 1980).
3.4.1. Dopamine and glutamate hypotheses Since many of the above-mentioned processes are disrupted in schizophrenia, prefrontal dysfunction, and in particular dysfunction of the dopaminergic innervation of the mPFC, is thought to be associated with the pathology of schizophrenia (Weinberger et al., 1986, 1988; Weinberger, 1987; Robbins, 1990; Deutch, 1992, 1993; Grace, 1991, 1992, 1993; Cummings, 1993; Lewis, 1995; Laruelle et al., 1996; Breier et al., 1997; Knable and Weinberger, 1997; Okubu et al., 1997; Akil et al., 1999; Laruelle and Abi-Dargham, 1999; Moore et al., 1999; Yang et al., 1999; Bertolino et al., 2000). This presumed association has spawned an enormous amount of research addressing the role of prefrontal cortical DA in these cognitive functions. It is important
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to mention, however, that another school of thought exists which posits that schizophrenia is not due to prefrontal dopaminergic dysfunction but rather to subcortical or cortical glutamatergic dysfunction (Kim et al., 1980; Javitt and Zukin, 1991; Schmidt, 1991; Sherman et al., 1991; Olney and Farber, 1995; Sams-Dodd, 1996; Steinpreis, 1996; Goff and Wine, 1997; HerescoLevy and Javitt, 1998; Jentsch and Roth, 1999; Bertolino et al., 2000; Glantz and Lewis, 2000). It is unclear if or how these two states relate to each other, given the strong interactions of both transmitter systems both cortically and subcortically. Nevertheless, systemically as well as at the level of the NAS/striatum DA and glutamate appear to have opposite effects on the activity of spiny neurons and on behavior (Carlsson and Carlsson, 1989a,b, 1990; Schmidt and Bubser, 1989; Elliott et al., 1990; Schmidt, 1991; Yukuro et al., 1991; Svensson and Carlsson, 1992; Ouagazzal et al., 1993; Iversen, 1995; Schmidt and Kretschmer, 1997). In line with this, it has been demonstrated that a stimulation of dopaminergic transmission as well as a blockade of glutamatergic transmission systemically or at the level of the NAS/striatum can produce psychotomimetic effects and cognitive disruption (Allen and Young, 1978; Sturgeon et al., 1979; Robinson and Becker, 1986; Schmidt, 1986; Burns and Lerner, 1976; McCullough and Salamone, 1992; Schmidt et al., 1992; Pierce and Rebec, 1993; Krystal et al., 1994; Ouagazzal et al., 1994; Steinpreis et al., 1994; Svensson et al., 1994a; Alkhatib et al., 1995; Carlezon and Wise, 1996a,b; Malhotra et al., 1996; Sams-Dodd, 1996; Verma and Moghaddam, 1996; Jentsch et al., 1997a,b). There is still some debate about the extent to which the effect of systemically administered glutamate antagonists is mediated indirectly via DA release in the NAS (Doherty et al., 1980; French, 1986a,b; Carboni et al., 1989; McCullough and Salamone, 1992; Steinpreis and Salamone, 1993; Jackson et al., 1994; Hertel et al., 1996). There is, however, evidence that the psychotomimetic and cognitive-disruptive effects of glutamate antagonists are at least partially independent of dopaminergic mechanisms (Keith et al., 1991; Carlsson and Carlsson, 1989a,b; Kitaichi et al., 1994; Ogawa et al., 1994; Ouagazzal et al., 1994; Ogren and Goldstein, 1994; Carlezon and Wise, 1996a; Druhan et al., 1996; Verma and Moghaddam, 1996; Waters et al., 1996; Adams and Moghaddam, 1998). In addition to the dopaminergic and glutamatergic systems, the prefrontal GABAergic system has also been implicated in schizophrenia (Simpson et al., 1989; Benes et al., 1991, 1992; Akbarian et al., 1995). But as in the case of the changes observed in prefrontal dopaminergic and glutamatergic transmission in schizophrenia, it is again not clear whether these alterations are the cause of the other observed changes and the symptomatology of schizophrenia or merely the
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(side-) effect of some other mechanism, be it dysfunction of the dopaminergic or glutamatergic system or another as yet unknown pathophysiological causal mechanism.
3.4.2. Prepulse inhibition The notion that schizophrenia involves a dysfunction of the mPFC (Weinberger, 1987) is also heavily based on findings from animal models of schizophrenia, in which mPFC lesions or intra-mPFC drug injections have been found to produce effects suggestive of schizophrenia-like symptoms. One of these animal models to assess sensorimotor gating mechanisms and information processing is prepulse inhibition (PPI) of the acoustic startle response in the rat (Braff and Geyer, 1990; Swerdlow et al., 1992a, 1994, 1995). PPI is the reduction of a startle response to an intense acoustic stimulus that is observed when this intense stimulus is preceded by a weaker, non-startling stimulus, or prepulse (Hoffman and Ison, 1980; Koch and Schnitzler, 1997; Swerdlow et al., 1992a; Swerdlow and Geyer, 1998; Koch, 1999). PPI is taken to model an organisms’ ability to ‘gate out’ or ‘filter out’ sensory and cognitive information, a process the disruption of which is considered to be an important feature in the symptomatology of schizophrenia (Nuechterlein and Dawson, 1984; Anscombe, 1987; Braff and Geyer, 1990). The interest in PPI as an animal model of schizophrenia arises mainly from the fact that PPI deficits can also be observed in schizophrenic patients (Braff et al., 1978, 1992; Swerdlow et al., 1994). Furthermore, PPI deficits can be induced by systemic administration of amphetamine or other DA agonists (Swerdlow et al., 1986; Koch, 1999) as well as PCP (Bakshi et al., 1994; Bakshi and Geyer, 1998), and the experimentally induced deficits as well as the deficits seen in schizophrenic patients can be reduced by neuroleptics (Bakshi et al., 1994; Koch and Bubser, 1994; Weike et al., 1999). DA in mPFC and NAS/striatum appears to have clear opposite roles with respect to its effects on PPI. Thus, drugs and treatments that decreased indices of dopaminergic activity in the mPFC have disruptive effects on PPI. For example, DA depletions by 6OHDA in the mPFC (Bubser and Koch, 1994; Koch and Bubser, 1994) and local mPFC injection of D1 and D2 receptor antagonists (Ellenbroek et al., 1996) were shown to disrupt PPI, while increases in dopaminergic activity in the mPFC had no effects on PPI (Swerdlow et al., 1986, 1990a,b, 1992b; but see Broersen et al. (1999) and Lacroix et al. (2000) who found that apomorphine injection into the mPFC disrupted PPI). Interestingly, systemic haloperidol treatment was able to reverse PPI deficits induced by 6-OHDA lesion of the mPFC (Koch and Bubser, 1994), and vice versa, intramPFC injection of haloperidol reversed PPI deficits induced by systemic apomorphine (Hart et al., 1998).
In contrast, various drugs and treatments that increase indices of dopaminergic activity in NAS or striatum have disruptive effects on PPI (Mansbach et al., 1988; Swerdlow et al., 1990a,b, 1992a; Wan and Swerdlow, 1993). Excitotoxic lesions of the mPFC that attenuate PPI (Yee, 2000) or that enhance the PPI-disrupting effects of low doses of apomorphine (Swerdlow et al., 1995) presumably do so via an increase in postsynaptic DA receptor sensitivity in subcortical areas (Jaskiw et al., 1990a; Braun et al., 1993), in analogy to what has been discussed above for the effects of such lesions on locomotion. This explanation may resolve the apparent paradox that 6-OHDA lesions of the mPFC (which presumably increase glutamatergic output from the mPFC) as well as excitotoxic lesions of the mPFC (which decrease glutamatergic output from the mPFC) produce increases in indices of dopaminergic activity, albeit apparently at two different levels. Thus, 6-OHDA lesions, by ‘disinhibiting’ excitatory input onto dopaminergic cells, increase subcortical measures of presynaptic DA activity (DA release, DA utilization) (Pycock et al., 1980b; Leccese and Lyness, 1987; Suzuki et al., 1995) and related behavioral measures (Robinson and Stitt, 1981; Joyce et al., 1983; Bubser and Schmidt, 1990; Jones and Robbins, 1992). On the other hand, excitotoxic lesions, by removing excitatory input onto dopaminergic cells, increases measures of postsynaptic DA activity (density, sensitivity and/or functional coupling of DA receptors) (Jaskiw et al., 1990a; Braun et al., 1993; Lipska et al., 1995; see also Christie et al., 1986) and related behavioral measures (Jaskiw et al., 1990a,b; Jaskiw and Weinberger, 1992; Braun et al., 1993; Lipska et al., 1995; see also Roberts et al., 1994; Wilkinson, 1997; Wilkinson et al., 1997). This increased postsynaptic dopaminergic activity does not seem to be due to an upregulation of the number or affinity of D1 or D2 receptors in the NAS or striatum (Jaskiw et al., 1991a) and may therefore involve changes in intracellular signalling and coupling of the receptors to second messenger systems (Mileson et al., 1991). In fact, a direct, antagonistic interaction between glutamatergic afferents and D1 receptor function in the striatum has been described (Reibaud et al., 1984; Halpain et al., 1990). Thus, removal of glutamatergic input to the striatum/NAS would relieve D1 receptor function from glutamate-mediated ‘inhibition’ and increase overall postsynaptic dopaminergic activity.
3.4.3. Latent inhibition Another example of behavioral inhibition processes is the phenomenon of latent inhibition (LI) where the repeated non-reinforced exposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement (Lubow, 1973; Lubow and Gewirtz, 1995). Thus, LI is considered to be an index of an organisms’ ability to ignore irrelevant stimuli, a
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process that is known to be disrupted in schizophrenia (Gray et al., 1991). As in the case of PPI, LI deficits can also be observed in acutely schizophrenic humans (Baruch et al., 1988; Gray et al., 1995; Lubow and Gewirtz, 1995), and these LI deficits can be modelled in experimental animals and in healthy humans by administration of amphetamine (Gray et al., 1992; Killcross et al., 1994; Thornton et al., 1996; Kumari et al., 1999); notably, in animal models the effects of systemic amphetamine are to a large extent mimicked by local infusions of the drug into the NAS (Solomon and Staton, 1982; Weiner et al., 1988; Kilcross and Robbins, 1993) and reversed by 6-OHDA lesions of the NAS and systemic or intra-NAS administration of haloperidol and other neuroleptic drugs (Weiner et al., 1990, 1996; Warburton et al., 1994; Gray et al., 1997). This suggests that LI deficits are primarily due to supra-normal DA transmission at the level of the NAS. In humans and animals neuroleptic treatment on its own potentiates LI effects, and it reverses LI deficits seen in schizophrenic patients (Weiner and Feldon, 1987; Christison et al., 1988; Feldon and Weiner, 1991; Williams et al., 1996; Trimble et al., 1997). It is interesting to note here, however, that the improvement of LI by neuroleptics is dose-dependent and that high doses of neuroleptics have been shown to disrupt rather than to enhance LI (Dunn et al., 1993; Kumari et al., 1999). This suggests that there may an optimal range of DA receptor activation for maximal LI and that deviation to below or above that range results in deficits in LI. This would be completely consistent with findings outlined in the next section that there appears to be an optimal and relatively narrow range of dopaminergic activity that is necessary for optimal cognitive performance. Interestingly, in contrast to the situation for PPI, in a search for the neural substrate of LI, no evidence for an involvement of the mPFC in LI mechanisms was found (Broersen et al., 1996; Ellenbroek et al. 1996; Joel et al., 1997; Lacroix et al., 1998, 2000). Thus, LI performance in rats was not affected by NMDA or electrolytic lesions of the mPFC, or injections of DA agonists and antagonists into that region. Rather, intact LI appears to depend on the integrity and normal functioning of the NAS and its inputs from the hippocampal formation and adjacent cortical areas (see Weiner, 1990; Weiner and Feldon, 1997, for review). Thus, it is somewhat difficult to reconcile the different lines of evidence in the context of LI as a model of schizophrenia. On the one hand, there is good evidence that LI has face validity and predictive validity as a model of schizophrenia, on the other hand the mPFC which is importantly involved in the etiology of schizophrenia does not seem to be part of the neuronal substrate mediating LI, questioning the construct validity of LI deficits as a model for schizophrenia.
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3.4.4. The relationship between dopaminergic tone and cogniti6e performance — the gating of information flow The potential role of the glutamatergic system nonwithstanding, the effects of mPFC DA on cognition appear to critically depend on the exact volume of dopaminergic transmission within a narrow range. Thus, an ‘inverted U-shape’ relationship between prefrontal cortical DA tone and cognitive performance has been described, with only some intermediate level of DA tone allowing for optimal performance while DA tones below or above that level disrupt performance (Brozoski et al., 1979; Sahakian et al., 1985; Sawaguchi and Goldman-Rakic, 1994; Murphy et al., 1996b; Zahrt et al., 1997; see Verma and Moghaddam (1996), Arnsten (1997) for further discussion). While in most of these aforementioned studies rather complex cognitive tasks in monkeys have been employed, in rat studies using the PPI and LI paradigms a rather similar picture of an optimal and narrow range of DA transmission for unimpaired cognitive performance has been delineated. Thus, in these paradigms it has also been found that enhancing as well as reducing DA in the mPFC can disrupt cognitive performance (see sections above). The particular relationship between dopaminergic tone and cognitive performance is also elegantly been demonstrated in a recent study by Granon et al. (2000). Here, rats were trained in a five-choice serial reaction time task. Subsequently, rats were divided into a group that achieved high baseline levels of accurate responding and into a group that achieved only low levels of accurate baseline responding. When the D1 receptor antagonist SCH23390 was infused into the prelimbic mPFC it was found that this drug selectively impaired the accuracy of attention performance in rats with high levels of baseline accuracy while having little effect in the group with low levels of baseline accuracy. Conversely, infusion of the D1 receptor agonist SKF38393 enhanced accuracy of attention performance in the low baseline group while having little effect in the high baseline group. Thus, the cognitive effects of DA (D1) agonists or antagonists in the mPFC depend on the quality of baseline performance, and under appropriate conditions manipulations of DA in the mPFC do not necessarily cause disruption of cognitive performance but can even improve poor performance. The D1 receptor also seems to be involved in the disrupting effects on cognitive performance of enhanced DA transmission. Thus, intra-mPFC infusion of the D1 agonist SKF81297 produced deficits in a delayed alternation task, an effect that could be antagonized by co-treatment with the D1 antagonist SCH23390 (Zahrt et al., 1997), although some evidence also exists that D2 receptors may be involved in the delayed alternation response impairment produced by ketamine (Verma and Moghaddam, 1996). Another elegant demonstra-
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tion of the relationship between dopaminergic tone and cognitive performance comes from another line of research. Acute exposure to stress can produce working memory deficits that can be ameliorated by treatments that reduce dopaminergic transmission (Murphy et al., 1996a,b; Arnsten and Goldman-Rakic, 1998). Given the high responsivity of the mesocortical DA neurons to stress (see section 2.2.2) this cognitive impairment during acute stress situations may be due to a hyperdopaminergic state in the PFC. On the other hand, Mizoguchi et al. (2000) showed that chronic stress also produces deficits in spatial working memory that is accompanied not by a hyperdopaminergic but rather by a hypodopaminergic prefrontal state. Interestingly in the present context, in the same study it was shown that intra-mPFC infusion of a D1 receptor agonist was able to reverse the working memory deficit. Furthermore, the hypodopaminergic prefrontal state in chronically stressed animals appeared to be largely due to reduced releasability of DA from presynaptic terminals in the mPFC since in these animals, unlike in control animals, it was not possible to stimulate DA release by infusion of KCl. Taken together, these results strongly suggest that hyper- as well as hypodopaminergic states in the mPFC (e.g. induced by acute or chronic stress, respectively) can produce working memory deficits that can be ameliorated by treatments that bring back the level of dopaminergic transmission to a ‘normal’ level, i.e. DA antagonists or DA agonists, respectively. These findings are in line with the notion of a predominant, although not exclusive, role of the D1 for mediating the effects of mPFC DA on cognition (Sawaguchi et al., 1990a,b; De Brabander et al., 1991; Sawaguchi and Goldman-Rakic, 1991, 1994; Arnsten et al., 1994; Smiley et al., 1994; Seamans et al., 1995b; Williams and Goldman-Rakic, 1995; Granon et al., 2000). The mechanism by which this ‘fine-tuned’ DA effect for optimum cognitive performance is achieved is not known but may be due to a ‘gating’ effect of DA in its interaction with other transmitters (in particular glutamate) in generating activity in prefrontal cortical pyramidal cells (Thierry et al., 1986; Smiley et al., 1994; Yang and Seamans, 1996; Yang et al., 1996a,b; Pirot et al., 1996; Bubser et al., 1997; Gulledge and Jaffe, 1998). According to this hypothesis, a too high tone of DA would ‘shut the gate’ for excitatory inputs onto pyramidal cells, and a too low tone of DA would facilitate ‘interferences’ between different inputs, both mechanisms leading to disruptions in cognitive performance. This view is indirectly supported by the finding that excitatory mediodorsal input and inhibitory input from the VTA converge on mPFC pyramidal cells and that the MD stimulation-evoked excitation in these cells can be blocked by simultaneous stimulation of the VTA (and also of the raphe nucleus, but of not of the locus
coeruleus, indicating that in this respect serotonin, but not noradrenaline, has similar effects as DA) (Ferron et al., 1984; Mantz et al., 1988, 1990; Thierry et al., 1990; Pirot et al., 1996). Furthermore, Bubser et al. (1997) showed that 6-OHDA lesions of the VTA increased intensity of Fos expression in the mPFC induced by pharmacological disinhibition of the mediodorsal thalamus, suggesting modulatory inhibitory effects of DA in the mPFC on glutamatergic transmission. Thus, information flow in the basal ganglia–thalamocortical circuit is under strong dopaminergic (and serotonergic, and, with respect to basal firing activity, also noradrenergic) control at the level of the mPFC. Furthermore, the dopaminergic mesocortical projection also exerts a potent modulatory influence on hippocampal input to the mPFC. Thus, DA not only inhibits spontaneous activity of mPFC neurons but also the excitation normally induced in these cells by stimulation of the hippocampus (Jay et al., 1995). In the same study it was also demonstrated that a population of mPFC neurons responding to hippocampal stimulation projects to the NAS and/or to the VTA, suggesting that the hippocampus can influence these subcortical areas via the mPFC and that DA can modulate this influence at the level of the mPFC. The role of the glutamatergic system for spatial working memory was also demonstrated by Romanides et al. (1999) who showed that not only an increased tone of prefrontal DA disrupted performance in a spatial delayed alternation task but also a decrease in glutamatergic tone that was achieved by intra-mPFC injections of the AMPA receptor antagonist CNQX or the NMDA receptor antagonist CPP, or by inhibition of glutamatergic afferents by injection of the GABA-B receptor agonist baclofen into the mediodorsal thalamus. As recently shown by Gurden et al. (1999), concurrent stimulation of the VTA at parameters known to produce DA release in the mPFC significantly enhances long-term potentiation (LTP) induced by stimulation of the hippocampo-prefrontal pathway. Conversely, electrolytic lesion of the VTA greatly reduced hippocampoprefrontal LTP. Given the important role of the hippocampus in learning and memory, it is obvious that this effect of mPFC DA on hippocampus-driven LTP may be an important element of its well documented role in memory function and cognitive processes. Yet, in the same series of experiments, Gurden et al. (1999) also found that, in contrast to the effects on LTP, VTA stimulation decreased the amplitude of postsynaptic responses of mPFC cells to hippocampal stimulation. Thus, DA not only has an important permissive influence on LTP in the mPFC, it also ‘gates’ hippocampal input to the mPFC independently of LTP mechanisms. A rather similar convergence of dopaminergic and glutamatergic inputs onto postsynaptic cells has also
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been demonstrated at the level of the NAS and striatum. Here, the dopaminergic axon terminals make contact with the necks of dendritic spines of spiny neurons and could therefore modulate the input from glutamatergic axon terminals which contact the heads of the same spines (i.e. the same ‘triad’ arrangement exists that has also been found in the mPFC for pyramidal cells, and dopaminergic and glutamatergic axon terminals) (Yang and Mogenson, 1984; Sesack and Pickel, 1990; Henriksen and Giacchiono, 1993; Mogenson et al., 1993; O’Donnell and Grace, 1994; Flores-Hernandez et al., 1997; Ce´peda et al., 1998; Ce´peda and Levine, 1998). In addition, terminals of mPFC efferents to the NAS/striatum not only converge onto spiny neurons with dopaminergic terminals but also with glutamatergic terminals of projections originating from amygdala, midline and intralaminar thalamic nuclei, entorhinal cortex and hippocampal complex (Kocsis et al., 1977; Pennartz and Kitai, 1991; O’Donnell and Grace, 1995; Finch, 1996). In fact, the degree of convergence is considerable, such that vitually none of the spiny neurons is innervated by only one of the different excitatory inputs. In particular, it has been shown that hippocampal input to NAS neurons can gate mPFC input to the same neurons (O’Donnell and Grace, 1995), and a gating of prefrontal cortical afferents of the NAS by afferents from the amygdala converging onto the same spiny neuron has also been described (Moore and Grace, 1996). From their findings, Grace and colleagues concluded that the hippocampus may provide a more ‘general-context dependent’ form of gating of information flow from the mPFC to the NAS, while the amygdala may provide a more discrete, ‘event-related’ form of gating of this information flow. This means that at the striatal level, information flow from the mPFC is not only modulated by converging dopaminergic input from the midbrain but also by converging glutamatergic input from the hippocampus, amygdala, and potentially other forebrain areas. These different glutamatergic inputs differ in the way they modulate each other, adding additional complexity and considerable computational power to the information processing at the level of the NAS. As mentioned above, the disruptive effects of NMDA receptor antagonists in mPFC-dependent cognitive tasks in rats and humans at low doses (Ghoneim et al., 1985; Morris et al., 1986; Parada-Turska and Turski, 1990; Wesierska et al., 1990; Krystal et al., 1994; Verma and Moghaddam, 1996) and the induction of psychotic symptoms in humans at higher doses has led to the idea that the functional deficits of schizophrenia might be even better modelled by the administration of NMDA receptor antagonists (such as PCP or ketamine) rather than by the administration of a DA agonist (Javitt and Zukin, 1991; Sams-Dodd, 1996, 1998a,b, 1999; Krystal et al., 1999; Lahti et al., 1999).
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The potent DA-releasing effects in the mPFC of highaffinity NMDA receptor channel blockers such as PCP or MK-801 may be central to their psychotomimetic and cognitive disrupting effects since memantine, a channel blocker with moderate affinity and high voltage dependency, that only weakly affects mPFC DA transmission (Bubser et al., 1992; Hesselink et al., 1999), has only weak psychotomimetic and cognitive disrupting effects in humans and in animal models of psychosis (Ditzler, 1991; Kornhuber et al., 1994; Danysz et al., 1997; Parsons et al., 1999). In fact, memantine is even used as a cognitive enhancer in dementia (Ditzler, 1991) and has been shown to improve learning in rats bearing entorhinal cortex lesions (Zajaczkowski et al., 1996). Thus, while the cognitive-behavioral effects of high affinity NMDA receptor antagonists appear to be dominated by their adverse effects which may be largely due to the mPFC DA release that these drugs produce, the beneficial cognitive-behavioral effects of channel blockers with low or moderate affinity are not masked or disrupted by the adverse effects brought about by DA release in the mPFC.
4. Functional heterogeneity of the mPFC as a possible cause for inconsistent data? It has been mentioned repeatedly throughout this review that manipulations of the mPFC have often yielded inconsistent results with respect to their behavioral and neurochemical effects. While different lesion techniques (e.g. ablation, excitotoxic, 6-OHDA, electrocoagulation), different neurochemical and physiological methods (e.g. ex vivo tissue analysis, in vivo microdialysis and voltammetry in anesthetized or freely moving animals, in vitro electrophysiology, in vivo electrophysiology in anesthetized or freely moving animals, different behavioral procedures and measures) may well account for many of the inconsistencies, another aspect that deserves further consideration is the anatomical and functional heterogeneity of the mPFC. Especially in the early studies (e.g. Richter and Hawkes, 1939; Zubek and De Lorenzo, 1952; Adler, 1961; Lynch et al., 1969, 1971; Glick, 1970, 1972; Lynch, 1970; Iversen, 1971; Iversen et al., 1971; Hannon and Bader, 1974; Kolb, 1974a,b), the various types of lesions (6-OHDA, electrolytic, excitotoxic, aspiration) often affected quite large but also variable regions of the frontal cortex and these often considerable variations in lesion location and lesion size (for 6-OHDA lesions this also includes the degree of DA depletion) must be kept in mind when discussing the apparently inconsistent results of these studies. In order to develop a more refined picture of the function of the mPFC (as well as other frontal cortical areas) it is without doubt necessary to employ more specific lesions, with respect to the size and local-
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ization of the lesion, and with respect to the neurotoxin employed in order to target specific types of cells while leaving other types of cells in the same area unaffected. The fact that the mPFC subareas (infralimbic, prelimbic, anterior cingulate, from ventral to dorsal) (van Eden and Uylings, 1985; Groenewegen et al., 1990; Uylings et al., 1990; van Eden et al., 1992) each have distinct afferent and efferent connections suggests that they are also functionally distinct. In brief, the infralimbic mPFC receives afferents from the hypothalamus, the VTA, amygdala, hippocampus and autonomic brain stem areas, but not from the MD (which is the reason why it is not considered as part of the mPFC by some authors). It sends projections preferentially to the NAS shell and the rostral MD, and also to the hypothalamus, amygdala and a number of autonomic brain stem nuclei. The prelimbic mPFC receives input from the rostral MD, the hippocampus, and the densest DA input from the VTA of all mPFC subdivisions. It projects preferentially to the NAS core and the rostral MD, and also to the VTA, basolateral amygdala, and other forebrain structures. The anterior cingulate mPFC receives afferents from the caudal MD, a number of neocortical areas, and also (to a small extent) the VTA, and projects preferentially to the dorsal striatum and the caudal MD, and to other neocortical and brainstem areas (Thierry et al., 1976b; Lindvall et al., 1978; Phillipson, 1979; Phillipson and Griffiths, 1985; Terreberry and Neafsey, 1987; Jay et al., 1989; Sesack et al., 1989; Conde´ et al., 1990, 1995; Groenewegen et al., 1990; Hurley et al., 1991; Berendse et al., 1992; Laubach and Woodward, 1995; Azuma and Chiba, 1996; Groenewegen et al., 1999). Assuming that this anatomical specificity and heterogeneity of the different mPFC subareas is also reflected in a functional differentiation and specificity of these subareas, it may well be that at least some of the inconsistencies in the literature concerning the function of the mPFC are due to experimental procedures which affected different mPFC subareas to a differential degree. Indeed, it is increasingly appreciated that the mPFC is not one single homogeneous entity but is comprised of several anatomically distinct subareas, and manipulations specifically restricted to individual subregions have shown that with a number of behavioral paradigms distinct functions of these subregions can be revealed (Kolb, 1974a; Sesack et al., 1989; Brito and Brito, 1990; Burns et al., 1993, 1996; Morgan et al., 1993; Granon et al., 1994; Mogensen and Holm, 1994; Granon and Poucet, 1995; Morgan and LeDoux, 1995; Seamans et al., 1995a; Delatour and Gisquet-Verrier, 1996; Kesner et al., 1996; Muir et al., 1996; Bussey et al., 1997a,b; Jinks and McGregor, 1997; Joel et al., 1997; Ragozzino et al., 1998; Tzschentke and Schmidt, 1998a,b,c, 1999, 2000a,b). However, from the publica-
tion years of these studies it is obvious that, with a few exceptions, the anatomical and functional heterogeneity has only very recently been widely appreciated and considered in the design of studies examining the function of the mPFC. This potentially high specificity of lesions effects is exemplified by our own studies which examined the effects of discrete subarea-specific excitotoxic quinolinic acid lesions on drug-induced reward as measured in the CPP paradigm, and behavioral sensitization. In these experiments it was found that morphine-induced CPP was blocked only by lesions of the whole mPFC or of the infralimbic subarea but not by lesions of the other subareas, while cocaine-induced CPP was blocked only by lesions of the whole mPFC or of the prelimbic subarea, but not by lesions of the other subareas. Remarkably, amphetamine-induced CPP was not affected by any of the lesions. Similar findings for cocaine and amphetamine were obtained in sensitization experiments, in that the development of cocaine-induced behavioral sensitization was blocked by lesions of the whole mPFC or of the prelimbic subarea but not by lesions of the other subareas. Also, the development of amphetamine-induced behavioral sensitization was not affected by any of the lesions. Furthermore, of the subarea-specific lesions, only lesions of the whole mPFC or the infralimbic subarea affected (i.e. reduced) spontaneous activity in a novel environment (Tzschentke and Schmidt 1998a,b,c, 1999, 2000a). A similar specificity of particular subareas within the mPFC in the context of sensitization was also found by other authors. Pierce et al. (1998) reported that only lesions of the dorsal, but not of the ventral aspects of the mPFC disrupt the expression of cocaine-induced sensitization. How can this apparent functional heterogeneity of the mPFC be explained? As mentioned above, there exists a topographical projection from the mPFC to the striatal complex. While the anterior cingulate mPFC projects preferentially to the dorsal striatum and the prelimbic mPFC projects preferentially to the NAS core, the infralimbic mPFC projects preferentially to the NAS shell (Berendse et al., 1992). For our observation that the infralimbic mPFC appears to be particularly important for the mediation of the rewarding effects of morphine it may be of relevance that the NAS shell expresses a higher density of mRNA for the m-opiate receptor than the NAS core or the dorsal striatum (Delfs et al., 1994; Mansour et al., 1995a,b) and in turn projects, via the ventral pallidum, to the PPTg (Heimer et al., 1991; Zahm and Heimer, 1993), a region also rich in m-receptors (Ding et al., 1996), that has been shown to be involved in opiate reward (Bechara and van der Kooy, 1989; Bechara et al., 1992). In addition, the infralimbic mPFC itself projects to and receives input from structures expressing rela-
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tively high densities of m-receptors, such as hippocampus, amygdala and autonomic brain stem nuclei (Hurley et al., 1991; Azuma and Chiba, 1996; Ding et al., 1996). Taken together, this evidence suggests that the infralimbic mPFC may be part of a circuitry that is particularly important for the mediation of morphine effects. Even if morphine does not initiate reward within the infralimbic mPFC, a possibility which is suggested by the fact that the mPFC contains only relatively low levels of m- and d-opioid receptors and preproenkephalin mRNA (Harlan et al., 1987; Bausch et al., 1995; Ding et al., 1996) and that the electrophysiological effects of morphine on mPFC neurons are mediated predominantly in afferent structures (Giacchiono and Henriksen, 1996), destruction of this site may disrupt the circuitry necessary for the development of morphine-induced CPP. In our own studies, cocaine-induced CPP was only disrupted by prelimbic and whole mPFC lesions, but not by infralimbic and anterior cingulate mPFC lesions. The observation that a lesion of the mPFC can disrupt the rewarding effects of cocaine is in line with a previous report (Isaac et al., 1989). We are unaware of any mapping study exploring the boundaries of cocaine self-injection sites within the mPFC, but the sites used in previous studies seem to have largely targeted the prelimbic subarea (Goeders and Smith, 1983, 1986, 1993; Goeders et al., 1986). The seemingly particular importance of the prelimbic mPFC may also be related to the fact that this part of the mPFC (along with the infralimbic mPFC) receives the densest dopaminergic innervation of all frontal cortical areas (Emson and Koob, 1978; Lindvall et al., 1978). In the same context it may also be of relevance that the prelimbic mPFC has a stronger projection to the VTA than the other mPFC subareas (Beckstead, 1979; Sesack et al., 1989; Hurley et al., 1991). To make things even more complicated, there is evidence that even within these different subregions functionally distinct subfields exist (Takenouchi et al., 1999), making it even more obvious that the localization of particular functions within the prefrontal cortex is highly specific and can only be accessed and assessed with anatomically equally specific methods.
5. Concluding remarks In summary, although the existing data is too heterogenous to draw a detailed general picture of the functional role of the mesocorticolimbic system, one general picture that emerges is that DA in the mPFC does not have an ‘executive’ function in the sense that dopaminergic signals in the mPFC become directly manifest as a concrete behavioral output or physiological response. Rather, the role of prefrontal cortical DA
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appears to be modulatory. This statement is primarily based on the common (but by no means consistent) finding that DA depletion of the mPFC does not cause any overt behavioral deficits and only few overt neurochemical alterations, as long as tests are conducted under ‘baseline’ conditions, i.e. in the absence of a behavioral of pharmacological challenge. If, however, an organism is challenged in a state of reduced mPFC DA transmission (induced either by 6-OHDA lesions or local injections of DA receptor antagonists) it becomes obvious that the mesocortical system usually acts in an inhibitory fashion on subcortical DA activity. This is then manifest in an increased behavioral and neurochemical response to an appropriate environmental or pharmacological challenge. The inhibitory influence of prefrontal cortical DA over various subcortical structures, including the NAS, has already been discussed extensively (Carlsson and Carlsson, 1990; Le Moal and Simon, 1991). Another point which deserves further consideration is the following: How is it possible that DA in the NAS has locomotor-inducing and rewarding effects while DA in the mPFC has also rewarding effects but has inhibitory effects on locomotion? This appears to be some kind of paradox, in particular when considered in light of the postulate that reward and locomotion are homologous manifestations of the same central brain mechanism (Wise and Bozarth, 1987). The first point that has to be addressed here is whether DA in the mPFC does really provide an essential reward signal. The only strong evidence for this comes from the series of studies by Goeders, Smith and collegues (Goeders and Smith, 1983, 1986; Goeders et al., 1986) demonstrating that cocaine and DA itself is self-administered into the mPFC, and that this cocaine self-administration is dependent on the dopaminergic innervation of the mPFC. All other evidence pointing to a role of prefrontal DA in reward is either not very strong or alternative interpretations are available to account for the findings. Furthermore, a number of findings argue against a crucial role of prefrontal DA in reward (see section 3.1). In several cases where an involvement of the mPFC in rewarding mechanisms has been demonstrated, the effects can in large part be explained without invoking prefrontal DA. Thus, the rewarding effects of self-administered NMDA-receptor antagonists in the mPFC demonstrated by Carlezon and Wise (1996a) are likely to be independent of DA and may be due to a disinhibition of pyramidal cells projecting to the VTA (via inhibition of mPFC GABAergic interneurons), or alternatively, to an inhibition of pyramidal cells projecting to the NAS. Both alternatives would lead to decreased activity in NAS spiny neurons, which is considered by some authors to be a common denominator of different reward signals converging onto the NAS (Wise, 1996a). Remarkably, as mentioned previ-
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ously, Goeders and Smith themselves have argued that cocaine in the mPFC produces effects resembling those observed after 6-OHDA lesions of the mPFC (Goeders and Smith, 1993). Clearly, this paradox awaits further examination and clarification. Based on the results of a series of studies, Di Chiara and collegues have suggested that the reinforcing efficacy of drugs of abuse is related to their ability to cause an increase in extracellular DA in the NAS but is unrelated to their effects on DA or NA release in the mPFC (Di Chiara et al., 1993; Di Chiara, 1995; Bassareo et al., 1996; Pontieri et al., 1996; Tanda et al., 1994, 1996, 1997). This suggestion was based on the observation that all drugs of abuse that were examined clearly showed stronger effects on NAS DA than on mPFC DA and that drugs that showed a preferential or exclusive effect on mPFC DA and/or NA (such as the selective NA reuptake blockers oxaprotiline and DMI) clearly do not have abuse potential. Taken together, although evidence that DA in the mPFC reduces locomotor activity (i.e. acts ‘antagonistically’ to subcortical DA) is very good, evidence that DA in mPFC directly mediates rewarding effects is weak, and the available data rather suggest that reward elicited within the mPFC (by drugs or stimulation) may be largely independent of DA within the mPFC. Thus, although the mPFC as such undoubtedly plays a rather important role in the brain reward system, the crucial reward-relevant elements in the mPFC are probably not the dopaminergic inputs but rather the pyramidal cells with their glutamatergic projections to the midbrain and possibly to the NAS. While DA in the mPFC may be sufficient to produce rewarding effects (at least in the case of cocaine), it is does not appear to be a necessary reward signal.
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Pharmacology and behavioral pharmacology of the mesocortical dopamine system T.M. Tzschentke * Gru¨nenthal GmbH, Research and De6elopment, Department of Pharmacology, Postfach 500444, 52088 Aachen, Germany Received 3 April 2000
Abstract The prefrontal cortex (PFC) has long been known to be involved in the mediation of complex behavioral responses. Considerable research efforts are directed towards refining the knowledge about the function of this brain area and the role it plays in cognitive performance and behavioral output. In the first part, this review provides, from a pharmacological perspective, an overview of anatomical, electrophysiological and neurochemical aspects of the function of the PFC, with an emphasis on the mesocortical dopamine system. Anatomy of the mesocortical system, basic physiological and pharmacological properties of neurotransmission within the PFC, and interactions between dopamine and glutamate as well as other transmitters within the mesocorticolimbic circuit are included. The coverage of these data is largely restricted to what is relevant for the second part of the review which focuses on behavioral studies that have examined the role of the PFC in a variety of phenomena, behaviors and paradigms. These include reward and addiction, locomotor activity and sensitization, learning, cognition, and schizophrenia. Although the focus of this review is on the mesocortical dopamine system, given the intricate interactions of dopamine with other transmitter systems within the PFC and the importance of the PFC as a source of glutamate in subcortical areas, these aspects are also covered in some detail where appropriate. Naturally, a topic as complex as this cannot be covered comprehensively in its entirety. Therefore this review is largely limited to data derived from studies using rats, and it is also specifically restricted to data concerning the medial PFC (mPFC). Since in several fields of research the findings concerning the function or role of the mPFC are relatively inconsistent, the question is addressed whether these inconsistencies might, at least in part, be related to the anatomical and functional heterogeneity of this brain area. © 2001 Elsevier Science Ltd. All rights reserved.
Contents 1. Introduction, aims and scope of the paper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. Pharmacology of the mesocortical dopamine system . . . . . . . . . . . . . . . . . . . 2.1. Anatomy of the mesocortical system . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. The dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Dopamine receptor distribution and localization . . . . . . . . . . . . . . . 2.1.3. The glutamatergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Other transmitter systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.1. The GABAergic system. . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.2. The noradrenergic system . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.3. Endogenous opioids. . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Basic physiological and pharmacological properties of neurotransmission within mPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Rates of activity of mesocortical dopaminergic neurons . . . . . . . . . . . 2.2.2. Responsivity to stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Tel.: +49-241-5692816; fax: + 49-241-5692852. E-mail address: [email protected] (T.M. Tzschentke). 0301-0082/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0301-0082(0 1)00033-2
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2.2.3. Responsivity to drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.1. Dopaminergic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.2. Glutamatergic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3.3. Neuroleptics and antidepressants . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Role of the NA transporter for the reuptake of DA. . . . . . . . . . . . . . . . . 2.2.5. Transmitter co-localization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Interactions between dopamine and glutamate, and other transmitters, within the mesocorticolimbic circuit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Dopamine–glutamate–GABA interactions in the prefrontal cortex . . . . . . . . 2.3.1.1. Dopaminergic regulation of prefrontal pyramidal cells and interneurons 2.3.1.2. Glutamatergic regulation of prefrontal dopaminergic afferents . . . . . . 2.3.2. Dopamine–glutamate–GABA – acetylcholine interactions in the VTA . . . . . . . 2.3.2.1. Glutamatergic regulation of VTA dopamine neurons . . . . . . . . . . . 2.3.2.2. Cholinergic regulation of VTA dopamine neurons . . . . . . . . . . . . . 2.3.2.3. The role of VTA GABAergic neurons . . . . . . . . . . . . . . . . . . . . 2.3.3. Dopamine–glutamate–GABA interactions in the NAS . . . . . . . . . . . . . . . 2.3.3.1. Glutamatergic regulation of accumbal spiny neurons. . . . . . . . . . . . 2.3.3.2. Glutamatergic regulation of accumbal dopaminergic afferents . . . . . . 2.3.3.3. Dopaminergic regulation of accumbal glutamatergic afferents . . . . . . 2.3.4. The ‘inverse’ relationship between cortical and subcortical dopamine . . . . . . .
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4. Functional heterogeneity of the mPFC as a possible cause for inconsistent data? . . . . . . .
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Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Behavioral pharmacology of the mesocortical dopamine system. . . . . . . . . . . . . . . . . 3.1. Reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Conditioned place preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.1. Intracranial self-administration . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.2. Lesion effects on intravenous self-administration . . . . . . . . . . . . . . 3.1.3. Self-stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Addiction and craving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Motor behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Effects of intra-mPFC drug injections . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Effects of mPFC lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.1. 6-OHDA lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.2. Excitotoxic lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Behavioral sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Alterations in DA release during repeated drug administration . . . . . . . . . . 3.3.2. Lesion effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Possible differential role of the mPFC in cocaine- versus amphetamine-induced sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Schizophrenia and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Dopamine and glutamate hypotheses. . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Prepulse inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Latent inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. The relationship between dopaminergic tone and cognitive performance — the gating of information flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nomenclature 5-HT 6-OHDA Ach AMPA CCK
5-hydroxytryptamine 6-hydroxydopamine acetylcholine a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid cholecystokinin
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CPP DA DAT DOPAC EPSP FR GABA GAD67 HVA ICSS IPSP LI MD MFB mPFC NA NAS NMDA PCP PD PFC PPI PPTg SNc THC TTX VTA
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conditioned place preference dopamine dopamine transporter dihydroxyphenylacetic acid excitatory postsynaptic potential fixed ratio g-amino-butyric acid glutamic acid decarboxylase homovanillic acid intracranial self-stimulation inhibitory postsynaptic potential latent inhibition mediodorsal medial forebrain bundle medial prefrontal cortex noradrenaline nucleus accumbens septi N-methyl-D-aspartate phencyclidine Parkinson’s disease prefrontal cortex prepulse inhibition pedunculopontine tegmental nucleus Substantia nigra pars compacta D9-tetra-hydro-cannabinol tetrodotoxin ventral tegmental area
1. Introduction, aims and scope of the paper For a long time, the frontal poles of the cerebral cortex have received considerable attention in both neurology and experimental neurobiology. This region of the brain is generally termed prefrontal cortex (PFC) and it is thought that this region is primarily involved in ‘higher order cognitive functions’. Unfortunately, such functions are not always readily accessible in experimental animals. Nevertheless, a large number of paradigms and tests have been developed that can be used to examine the function of this region in rats, primates and other species. The major aim of this review is to provide a broad overview of what is known about the functional anatomy and pharmacology of the PFC and of work that has examined the functions of the PFC using behavioral pharmacological methods. The present review will focus primarily on rat studies. There is considerable debate about cross-species homologies of different frontal cortical areas, and discussion of this issue and the comprehensive consideration of data from other species would be beyond the scope of this review. Dopaminergic innervation of the PFC shows considerable cross-species differences, in particular there are substantial differences between rodents and primates with respect to the anatomical distribution of dopamine (DA) input but also with respect to
the expression of different DA receptor subtypes (Berger et al., 1991). Therefore, whenever possible and unless stated otherwise, the great majority of the data reviewed in this paper is derived from rat studies. Nevertheless, data from selected primate studies will be cited when this seems appropriate and where it helps to illustrate certain examples in cases where rat data is too limited to allow for general statements. Yet, the aim of this review is not to systematically compare and discuss rat and primate data. There exists a considerable number of topical as well as comprehensive reviews concerning the PFC, and I will refer to these reviews where appropriate, especially in cases where reference is made to early studies, or in cases where topics are touched which are of relevance for the present context but where it would be beyond the scope and the space limits of this review to cover the literature in detail. Furthermore, generally the focus of this review is on the coverage of data collected over the last two decades. Earlier studies are also included where necessary and meaningful, but much of this literature is covered by referring to appropriate review articles. A particular emphasis is put on the description of the anatomical and functional characteristics of the mesoprefrontocortical dopaminergic projection to the extent to which they are different from those of the mesoaccumbal/nigrostriatal dopaminergic projection. There-
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fore, it will be necessary to also cover the features of the latter projections in some detail. However, in contrast to the description of the mesocortical system the description of the mesolimbic system will not be comprehensive but will rather be limited to some selected, representative studies. The discussion of transmitter systems will largely be restricted to DA, glutamate, and GABA which does not mean to imply that other transmitter systems such as noradrenaline (NA), acetylcholine (Ach), serotonin (5-HT) and a number of peptide transmitters and neuromodulators such as the endogenous opioids, substance P, neurotensin, cholecystokinin (CCK) and others do not play an important role in PFC function. Nevertheless, it would be beyond the scope of this review to include all neurochemical aspects concerning the PFC, and in particular the numerous and complex interactions of the other transmitter systems with each other and with the dopaminergic, glutamatergic and GABAergic systems. For example, one transmitter system that is covered only superficially in this review is the serotonergic system, to the extent that prefrontal serotonergic mechanisms are thought to be involved in the action of atypical neuroleptic drugs. Serotonin undoubtedly plays an important role in the function of the PFC, but it would be beyond the scope of this paper to cover this large and complex literature in detail. Also, no attempt is made in this review to cover each and every aspect of the multitude of functions of the PFC. For example, areas that are not covered in this paper include the role of the PFC in autonomic regulatory processes, in emotionality and in social behavior. A very important point is that, whenever possible, the discussion in this review is restricted to the medial prefrontal cortex (mPFC). Other frontal cortical areas which are also considered to be part of the PFC such as the sulcal prefrontal cortex are deliberately not included in this review. Unfortunately, in many studies the anatomical specificity of experimental manipulations of the PFC is not entirely clear. Especially in many early studies lesions or local drug injections often affected large, ill-defined areas of the frontal cortex, i.e. various frontal cortical areas other than the mPFC. Whenever possible, the discussion in the present review is centered on studies that clearly focussed on the mPFC, particularly in the rat. The first main part of this review will give an overview of the pharmacology of the mesocortical dopamine system, including a summary of the anatomical organization of the dopaminergic system in relation to other transmitter systems, a summary of the basic physiological and neurochemical features of the mesocorticolimbic system, and of the functional relevance of the interactions of different transmitter systems within the mesocorticolimbic system. The second major part of the review will then address the functions of the mesocortical dopamine system as assessed with behavioral pharmacological
methods in experimental animals. This overview will cover the role of the mPFC in reward and addiction, motor behavior and sensitization, and schizophrenia, learning and cognition. Before concluding the review, a brief section will examine the possibility that the often inconsistent findings concerning the functional role of the mPFC may be due to the anatomical and functional heterogeneity of this brain region. 2. Pharmacology of the mesocortical dopamine system
2.1. Anatomy of the mesocortical system 2.1.1. The dopaminergic system Dopaminergic projections to the mPFC arise predominantly in the VTA (and to a small extent in the medial SNc) and innervate predominantly the infralimbic and prelimbic subareas, while the dopaminergic innervation of the anterior cingulate subarea is less prominent (Thierry et al., 1973; Fuxe et al., 1974; Ho¨kfelt et al., 1974; Beckstead, 1976; Berger et al., 1976; Simon et al., 1976, 1979a; Carter and Fibiger, 1977; Tassin et al., 1977, 1978a; Bjo¨rklund et al., 1978; Lindvall et al., 1978; Moore and Bloom, 1978; Beckstead et al., 1979; Haglund et al., 1979; Albanese and Bentivoglio, 1982; Swanson, 1982; Albanese and Minciacchi, 1983; Bjo¨rklund and Lindvall, 1984; Serrano et al., 1986; Oades and Halliday, 1987; Reader and Grondin, 1987; van Eden et al., 1987; Garris et al., 1993; Carr et al., 1999; Hedou et al., 1999). DA innervation of the mPFC shows a laminar distribution, with the deep layers (V, VI) receiving a denser dopaminergic input than the more superficial layers (Emson and Koob, 1978; Descarries et al., 1987; van Eden et al., 1987; Berger et al., 1988, 1991; Ciliax et al., 1995). This is consistent with the preferential occurrence of D1 and D2 receptors in these layers (Klemm et al., 1979; Dawson et al., 1985, 1986a,b; Dubois et al., 1986; Savasta et al., 1986; Charuchinda et al., 1987; Richfield et al., 1989; Mansour et al., 1990, 1991; Fremeau et al., 1991; Mengod et al., 1991; Huang et al., 1992; Vincent et al., 1993, 1995; Gaspar et al., 1995). Cortical pyramidal cells appear to be the primary targets of dopaminergic afferents to the mPFC (van Eden et al., 1987; Se´gue´la et al., 1988; Goldman-Rakic et al., 1989; Verney et al., 1990) although D1 and D2 receptors are also located on cells other than pyramidal cells in the mPFC (presumably GABAergic interneurons) (Vincent et al., 1993), and DA terminals also make contact with non-pyramidal, GABAergic cells (Verney et al., 1990; Benes et al., 1993; Sesack et al., 1995a,b). In fact, Vincent et al. (1995) have suggested that while D2 receptors are expressed in both pyramidal and nonpyramidal cells, D1 receptors may be expressed predominantly in nonpyramidal cells. With respect to the dopaminergic input onto pyramidal cells, it has been shown that dopaminergic boutons form symmetric (i.e. presumably inhibitory) synapses
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on dendritic spines of pyramidal cells. Asymmetric (i.e. presumably excitatory) synapses, probably originating from thalamo–cortical or cortico – cortical inputs, are often found in close apposition to the dopaminergic synapse on the same dendritic spine, while direct axo– axonic synapses are not observed (Goldman-Rakic et al., 1989; Smiley et al., 1992; Smiley and Goldman-Rakic, 1993; DeFelipe and Farinas, 1992). This ‘triad’ arrangement would be well suited to subserve the ‘gating’ function of DA on information flow mediated by glutamatergic neurotransmission (see section 3.4.4). From this ‘circuit perspective’ it is also interesting to note that DA terminals in the mPFC make direct contact with pyramidal cells that project to the NAS (Carr et al., 1999). Thus, the VTA can monosynaptically influence glutamatergic transmission in the NAS which may in turn presynaptically regulate DA transmission in the mPFC (see section 2.3). Different lines of anatomical, physiological and pharmacological (see section 2.1.2) evidence suggest that mesocortical and mesoaccumbal dopaminergic projections consist of two distinct populations of DA neurons. The cell bodies of these two neuronal populations are at least in part separated into distinguishable anatomical domains at the level of the VTA. Cells located in the nucleus paranigralis of the VTA predominantly project to subcortical sites, whereas cells located in the nucleus parabrachialis pigmentosus predominantly project to cortical sites, including the medial prefrontal cortex (Berger et al., 1976; Lindvall et al., 1978; Palkovits et al., 1979; Simon et al., 1979a; Deniau et al., 1980; Fallon, 1981; Slopsema et al., 1982; Swanson, 1982; Albanese and Minciacchi, 1983). Furthermore, VTA efferents to the mPFC and the NAS show only a relatively small degree of collateralization to other terminal regions such as striatum, septum, and entorhinal cortex (Lindvall et al., 1974, 1977; Fallon, 1981; Fallon and Loughlin, 1982; Swanson, 1982; Loughlin and Fallon, 1984; Sobel and Corbett, 1984). A fact emphasized by Swanson (1982) that has often been overlooked or neglected in functional – anatomical considerations of the transmitter interactions within the mesocorticolimbic circuit is that the VTA contains a considerable number of non-dopaminergic cells that project largely to the same terminal regions as the dopaminergic cells. For example, only 30% of the VTA-prefrontal projection is dopaminergic, while 85% of the VTA–NAS projection contains DA. Thus, in particular when considering the influence of the VTA on the mPFC these non-dopaminergic neurons may play a very important role, yet the current discussion in the literature centers almost exclusively on the dopaminergic part of this projection. There is good evidence that the non-dopaminergic part of the projection from the VTA to the mPFC is inhibitory and contains GABA as its transmitter (Thierry et al., 1980; Albanese
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and Bentivoglio, 1982; Swanson, 1982; Ferron et al., 1984; Gillham et al., 1990; Steffensen et al., 1998). This GABAergic projection may be important when considering the effects of VTA stimulation on mPFC cells (see section 2.3.2). As mentioned above, the VTA–NAS projection appears to be largely dopaminergic. Nevertheless, there is evidence that the non-dopaminergic part (15%, according to Swanson, 1982) of the projection from the VTA to the NAS/striatum is also GABAergic and appears to terminate predominantly on and modulates the activity of cholinergic interneurons which in turn input to medium spiny neurons (Pickel et al., 1988; Pickel and Chan, 1990; Rada et al., 1993; van Bockstaele and Pickel, 1995). Although cholinergic interneurons in the NAS/striatum are few in numbers, they can exert potent modulatory effects on the spiny GABAergic projection neurons. Thus, the relatively small GABAergic input from the VTA could nevertheless make an important contribution to the overall activity of striatal output. To make the picture even more complicated, GABA may also be co-localized with DA in some midbrain neurons projecting to the NAS/striatum (Kosaka et al., 1987).
2.1.2. Dopamine receptor distribution and localization DA receptors of the D1-type as well as of the D2type are present in the mPFC although their distribution shows only partial overlap (Scatton and Dubois, 1985; Dawson et al., 1986a,b; Bouthenet et al., 1987; Nisoli et al., 1988; Goldman-Rakic et al., 1990) and the density of D2 receptors appears to be considerably lower than that of D1 receptors (Liskowski and Potter, 1985; Martres et al., 1985; Boyson et al., 1986; Camus et al., 1986; Charuchinda et al., 1987; MeadorWoodruff and Mansour, 1991; Gaspar et al., 1995). This is consistent with the finding that the expression of D2 receptors is largely restricted to corticostriatal and corticocortical neurons in layer V while D1 receptors are found in layers II, V, and VI, and in corticostriatal, corticocortical but also in corticothalamic neurons (Goldman-Rakic et al., 1990; Vincent et al., 1993; Gaspar et al., 1995; Deutch et al., 1996; Lu et al., 1997b). The majority of D1 and D2 receptors within the mPFC appears to be located on pyramidal cells, but there is evidence that both receptor subtypes are also located on GABAergic interneurons (Al-Tikriti et al., 1992; Vincent et al., 1993, 1995; Smiley et al., 1994; Deutch et al., 1996; Grobin and Deutch, 1998) and on the terminals of afferents from the VTA (Fadda et al., 1984; see Gaspar et al., 1995). This receptor population may comprise the release-regulating autoreceptors discussed in section 2.2.1. There appears to be a good correlation between the overall cortical distribution of D1 and D2 receptor binding sites and the expression of the respective mRNA for these receptors (Choi et al., 1995), suggesting that the large majority of the receptors are
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located on cell bodies and dendrites of cells intrinsic to the mPFC and not on presynaptic axon terminals of mPFC afferents. Sesack and Bunney (1989) presented evidence that the D2-type receptor mediating the inhibitory effects of DA in the mPFC has pharmacological properties different from other D2 receptor populations. Initially, it was suggested that the receptors in question might actually be of the D3 or the D4 subtype (Sokoloff et al., 1980), but subsequently only very low levels of mRNA for D3 (Sokoloff et al., 1990; Bouthenet et al., 1991), D4 (van Tol et al., 1991) as well as D5 (Sunahara et al., 1991; Laurier et al., 1994) receptors have been found in the rat. On the other hand, using autoradiographic and, in particular, immunocytochemical methods, high levels of the D4 receptor subtype were found in the frontal cortex of rats (Ariano et al., 1997; Defagot et al., 1997; Tarazi et al., 1997). Interestingly, data from humans and non-human primates suggest that here the D1 and D4 receptor subtypes are the most abundant of all DA receptors expressed in frontal cortical areas. In fact, it appears that the prefrontal cortex is the only brain area with appreciable levels of D4 receptors in the primate brain, including humans (Corte´s et al., 1989; MeadorWoodruff et al., 1989, 1996; Lidow et al., 1991, 1998; Matsumoto et al., 1996). These D4 receptors may be at least in part located on GABAergic interneurons rather than on pyramidal cells (Mrzijak et al., 1996). The specificity of D4 receptor location in frontal cortical areas is also supported by the finding that peripheral administration of a D4 receptor antagonist induces c-fos expression only in the prefrontal cortex within the forebrain (Merchant et al., 1996; Feldpausch et al., 1998). The relative restriction of D4 receptors to the prefrontal cortex has raised hopes that specific ligands for these receptors may be effective in the treatment of mental diseases such as schizophrenia which are thought to involve prefrontal dysfunction (see section 3.4), without having prominent motor or other side effects. Unfortunately, the first selective ligands for this receptor entering clinical trials have proven to be ineffective in the treatment of schizophrenia (Kramer et al., 1997).
2.1.3. The glutamatergic system The main transmitter of the efferent mPFC projections is thought to be glutamate (Spencer, 1976; Divac et al., 1977; Kim et al., 1977; McGeer et al., 1977; Carter, 1980, 1982; Godukhin et al., 1980; Fonnum et al., 1981; Walaas, 1981; Druce et al., 1982; Hassler et al., 1982; Fonnum, 1984; Koller et al., 1984; Kornhuber et al., 1984; Ottersen and Storm-Mathissen, 1984; Christie et al., 1985a,b, 1987; Sandberg et al., 1985; Girault et al., 1986a; Young and Bradford, 1986; Butcher and Hamberger, 1987; Palmer et al., 1989; DeFelipe and Farinas, 1992; Ray et al., 1992).
The mPFC is not only the origin of a number of prominent glutamatergic projections but also receives considerable excitatory, glutamatergic input from cortical and subcortical sources. The most prominent of the cortical afferents originates from the contralateral mPFC, and the most prominent of the subcortical afferents originates from the mediodorsal thalamus (Leonard, 1969; Krettek and Price, 1977; Divac et al., 1978; Groenewegen, 1988; Groenewegen et al., 1990; Conde´ et al., 1990, 1995; Barbas et al., 1991; Gigg et al., 1992; Ray and Price, 1992; Kuroda et al., 1993; Pirot et al., 1994, 1995; Gioanni et al., 1999). In fact, the prefrontal cortex has been defined in the literature as the cortical region receiving afferents from the mediodorsal thalamus (Rose and Woolsey, 1948; Divac et al., 1993; Kuroda et al., 1998; see Uylings and van Eden, 1990; Groenewegen et al., 1997, for further discussion). Other prominent glutamatergic inputs to the mPFC have also been described, e.g. from the hippocampus (Jay et al., 1992; Conde´ et al., 1995; Carr and Sesack, 1996) and the amygdala (Groenewegen et al., 1990; Kita and Kitai, 1990; Bacon et al., 1996). A direct interaction between DA and glutamate in the mPFC is supported by the observation that dopaminergic and glutamatergic terminals are localized in close apposition to each other on the same postsynaptic pyramidal cell in the mPFC (Goldman-Rakic et al., 1989; Verney et al., 1990; Smiley and Goldman-Rakic, 1993; Pickel and Sesack, 1995; Carr and Sesack, 1996; Kuroda et al., 1995, 1996) such that presynaptic as well as postsynaptic interactions could be possible (see section 2.3.1 for further discussion). The prefrontal cortex is a cortical region particularly rich in NMDA and AMPA receptors (Monaghan et al., 1984; Monaghan and Cotman, 1985; Sakurai et al., 1991; Martin et al., 1993; Petralia et al., 1994a,b), and most if not all pyramidal cells appear to express both types of receptors (Pirot et al., 1995). Glutamatergic input to the mPFC is a crucial determinant of pyramidal cell activity. As mentioned above, the MD thalamus provides an important source of cortical glutamate. In addition, mPFC efferents form collaterals that feed back onto pyramidal cells. Interestingly, these two glutamatergic inputs can be differentiated on the basis of the type of glutamate receptor that mediates their effects and of how these inputs are modulated by DA. As Pirot et al. (1995) have shown, thalamic input to pyramidal cells is almost entirely mediated by AMPA receptors while input from recurrent collaterals is largely mediated by NMDA receptors, but to a small degree also by AMPA receptors. The same group (Pirot et al., 1996) has also shown that the direct thalamic input is not affected by local DA application or concurrent stimulation of the VTA while the excitation generated by input from recurrent collaterals is inhibited by increased DA.
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An additional interesting anatomical and functional distinction between these two glutamate receptor types has been found by Zhang and Shi (1999). They reported that in a slice preparation dendritic focal glutamate application induced repetitive bursts in most cells tested. On the other hand, in the same cells, somatic focal glutamate application induced only regular spiking but no burst activity. The bursting induced by dendritic glutamate could be reduced by both the NMDA receptor antagonist CGP37849 and the AMPA receptor antagonist NBQX, suggesting that NMDA as well as AMPA receptors are involved in the generation of the burst activity. However, selective activation of dendritic AMPA receptors by AMPA produced only regular spiking while selective activation of dendritic NMDA receptors by NMDA largely mimicked the burst-inducing effects of glutamate. These data suggest that burst activity in layer V/VI mPFC pyramidal cells is induced only by glutamatergic input onto dendrites but not onto the cell body. They also suggest that both NMDA and AMPA receptors are activated during dendritic glutamate activation, but that the bursting effect is primarily mediated by NMDA receptors. An apparently common feature of most corticolimbic and basal ganglia structures is that reciprocal connections exist between them and that in addition many structures are interconnected directly or indirectly. For example, while the VTA sends dopaminergic projections to the mPFC and NAS, the mPFC sends glutamatergic projections to the VTA and also to the NAS (Powell and Leman, 1976; Beckstead, 1979; Phillipson, 1979; Carter, 1982; Koller et al., 1984; Phillipson and Griffiths, 1985; Christie et al., 1985a,b, 1987; Girault et al., 1986b; Sesack et al., 1989; Berendse et al., 1992; Sesack and Pickel, 1990, 1992; Smith et al., 1996; Gorelova and Yang, 1997; Carr et al., 1999). These projections have a clear topographical organization (Sesack et al., 1989; Berendse et al., 1992; Zeng and Stuesse, 1993). For example, the dorsal parts of the mPFC (anterior cingulate and dorsal prelimbic area) project preferentially to the striatum and also to the dorsal aspects of the NAS, while the ventral parts of the mPFC (ventral prelimbic and infralimbic area) project preferentially to the ventral aspects of the NAS (Sesack et al., 1989). Dopamine – glutamate interactions at the level of the NAS/striatum are suggested by the finding that dopaminergic efferents from the VTA and glutamatergic efferents from the mPFC terminate in close apposition to each other, often on the same spine of the postsynaptic cell in the NAS/striatum (Bouyer et al., 1984; Freund et al., 1984; Sesack and Pickel, 1992). Interestingly, mPFC projections to the VTA synapse on dopaminergic as well as on non-dopaminergic cells, and the latter contacts may even be more numerous than the former (Sesack and Pickel, 1992; Smith et al., 1996). On the other hand, efferents from the mPFC
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have also been shown to directly contact DA neurons in the VTA that project to the NAS (van Eden and Feenstra, 1997). The consideration of these findings may be very important when discussing the behavioral and neurochemical effects of mPFC manipulations. Finally, the NAS sends GABAergic projections to the VTA and/or substantia nigra pars reticulata which, in turn, via thalamic nuclei, project back to the mPFC (Nauta et al., 1978; Phillipson, 1979; Walaas and Fonnum, 1980; Groenewegen and Russchen, 1984; Groenewegen, 1988; Ray and Price, 1992; Deniau et al., 1994). Furthermore, a direct feedback loop between the mPFC and the MD thalamus has also been described, such that fibers from the MD thalamus synapse on pyramidal cells in the mPFC that project back to the MD thalamus (Kuroda et al., 1993). Thus, on a ‘systems’ level, the mPFC and adjacent regions of the frontal cortex are parts of various partly parallel and functionally segregated, partly interconnected basal ganglia–thalamocortical circuits. A detailed anatomical and functional consideration of these circuits is beyond the scope of this present paper, therefore the interested reader is referred to a number of comprehensive reports and reviews on this topic (Alexander et al., 1986, 1990; Groenewegen et al., 1990; Parent, 1990; Gerfen, 1992; Zahm and Brog, 1992; Joel and Weiner, 1994, 1997; Pennartz et al., 1994; Houk and Wise, 1995; Parent and Hazrati, 1995; Wright and Groenewegen, 1995, 1996; Montaron et al., 1996; Maurice et al., 1997, 1998a,b, 1999; Lavin and Grace, 1998; Smith et al., 1998; Groenewegen et al., 1999).
2.1.4. Other transmitter systems 2.1.4.1. The GABAergic system. A very important element in the mPFC are the GABAergic interneurons (Ottersen and Storm-Mathissen, 1984; Esclapez et al., 1987). The available data suggest a rather complex mutual interplay of synaptic modulation of GABAergic, dopaminergic and glutamatergic neurotransmission within the mPFC (see section 2.3.1 for a more detailed account of these regulatory interactions). The picture is further complicated by the fact that these GABAergic interneurons do not constitute a homogenous cell population but comprise different, morphologically and functionally distinct cell populations (Kawaguchi and Kubota, 1993, 1996; Kawaguchi, 1993, 1995; Deutch and Duman, 1996; Sesack et al., 1998b). Direct (presumably mutual) synaptic connections exist between pyramidal cells and interneurons (DeFelipe and Farinas, 1992), and interneurons have been shown to possess NMDA receptors, AMPA/kainate receptors, and DA receptors of the D1 as well as of the D2 receptor family (Huntley et al., 1994; Mrzijak et al., 1996; Muly et al., 1997). Thus, these interneurons are intricately involved in mPFC synaptic interactions.
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2.1.4.2. The noradrenergic system. The mPFC also receives a dense noradrenergic innervation originating from the locus coeruleus (Foote et al., 1983; Bjo¨rklund and Lindvall, 1986), and DA and NA have been shown to interact in a number of ways although there appears to be only a partial overlap between dopaminergic and noradrenergic terminals. DA terminals are found mainly in the deeper layers of the mPFC while NA terminals are found mainly in the more superficial layers of the mPFC (Bjo¨rklund and Lindvall, 1984; Moore and Card, 1984). The mPFC has a relatively high density of a2-receptors (Talley et al., 1996) which may primarily be located presynaptically to regulate the release of DA (Ueda et al., 1983) and NA (Dennis et al., 1987). Prominent functional pre- and postsynaptic interactions between DA and NA have been determined and will be discussed in subsequent sections. 2.1.4.3. Endogenous opioids. Another transmitter system to be considered in the context of neural transmission within the mPFC is the endogenous opioid system which may be of particular relevance for mechanisms of motivation and reward (see section 3.1). Relatively high levels of d-receptors and somewhat lower levels of mand k-opioid receptors as well as their corresponding mRNAs are expressed in the mPFC with a clear laminar distribution, although less is known about the distribution of these receptors at the cellular level (Mansour et al., 1987, 1988, 1994, 1995a; Ding et al., 1996). Delfs et al. (1994), Mansour et al. (1995b) found a mismatch of m-receptor binding sites such that relatively high levels of m-receptors were found in the anterior cingulate and other cortical areas in the absence of in situ hybridization staining for the corresponding mRNA. This may suggest that cortical m-receptors are primarily located presynaptically on terminals of afferent neurons, which would be consistent with the finding that m-agonists can presynaptically modulate release of NA in a cortical slice preparation (Chesselet, 1984). m-opioid agonists can clearly influence synaptic transmission (Heijna et al., 1990; Wood and Rao, 1991; Vezina et al., 1992) and cell firing (Tanaka and North, 1994; Giacchiono and Henriksen, 1996) in the mPFC, although this latter effect of systemically administered opioids may in large part be indirectly mediated by the action of the drugs in other brain areas rather than directly by the action on opiate receptors within the mPFC (Giacchiono and Henriksen, 1996). The findings concerning the consequences of mPFC manipulations for the behavioral effects of opiates are inconsistent (see sections below), therefore it is not clear to what extent opioid receptors within the mPFC contribute to the overall behavioral effects of systemically administered opiates.
2.2. Basic physiological and pharmacological properties of neurotransmission within the mPFC A number of striking as well as subtle particularities of the mesocortical DA projection as compared to subcortical DA projections have been described in the literature. Many of these particularities relate to the basic physiological, pharmacological and functional properties of mesocortical dopaminergic cells and the manner in which they release DA in the mPFC.
2.2.1. Rates of acti6ity of mesocortical dopaminergic neurons The DA innervation of the mPFC is less dense than that of the NAS/striatum in terms of absolute extracellular basal DA levels and tissue DA content (Kolb, 1984; Plantje et al., 1987; Garris et al., 1993; Ihalainen et al., 1999). It has been shown at the cell body level in the VTA and at the axon terminal level in the mPFC that mesocortical DA neurons express lower levels of DA reuptake transporter sites than mesoaccumbal DA neurons (Javitch et al., 1985; Mennicken et al., 1992; Shimada et al., 1992; Ciliax et al., 1995; Freed et al., 1995; Nirenberg et al., 1997a,b; Sesack et al., 1998a). Related to this may be the finding that DA can diffuse over a longer distance and is cleared less rapidly from the extracellular space in the mPFC as compared with NAS or striatum (Garris et al., 1993; Garris and Wightman, 1994; Cass and Gerhardt, 1995; Lee et al., 1996). Also, the ratio of extracellular DA to whole tissue DA is higher than in other forebrain structures, which may be related to the higher relative rates of turnover and release, and/or lower relative rates of reuptake of DA observed in the mPFC as compared to other DA terminal regions (Bannon et al., 1981; Anden et al., 1983a; Sharp et al., 1986a; Hoffmann et al., 1988; Maisonneuve et al., 1990; Garris et al., 1993; Garris and Wightman, 1994). The higher relative rates of release, in turn, may be due to the higher basal firing rates, including more burst activity, and the more efficient stimulation-release coupling of mesofrontal DA neurons (Bannon and Roth, 1983; Chiodo et al., 1984; White and Wang, 1984; Chiodo, 1988; Hoffmann et al., 1988) and also to the fact that these neurons do not possess DA synthesis-modulating and impulse-regulating autoreceptors (Bannon et al., 1980, 1981, 1982, 1983; Anden et al., 1983b; Chiodo et al., 1984; Galloway et al., 1986; Wolf et al., 1986; Wolf and Roth, 1987; Hoffmann et al., 1988), although there is good evidence that they do carry DA release-modulating autoreceptors (Shepard and German, 1984; Galloway et al., 1986; Talmaciu et al., 1986; Altar et al., 1987; Plantje et al., 1987; Wolf and Roth, 1987; Hoffmann et al., 1988; Cubeddu et al., 1990; Bean and Roth, 1991; Fedele et al., 1993). On the other hand, clear evidence exists that dopaminergic transmission in the NAS and
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striatum is under strong autoreceptor control at various levels (modulation of release, synthesis, impulse-flow) (Groves et al., 1975; Aghajanian and Bunney, 1977; Nowycky and Roth, 1978; Starke et al., 1978; Roth, 1979; Skirboll et al., 1979; Kamal et al., 1981; Bannon et al., 1982; Cubeddu and Hoffmann, 1982; Haubrich and Pflueger, 1982; Hoffmann and Cubeddu, 1982; Parker and Cubeddu, 1985; Hoffmann et al., 1986, 1988). Furthermore, mesocortical DA neurons appear to express higher levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA biosynthesis (Bayer and Pickel, 1990; Blanchard et al., 1994), which may be related to the absence of synthesis-regulating autoreceptors and the high rates of release of DA in the mPFC. Also, mesocortical DA neurons are distinguished from mesoaccumbal DA neurons at the cell body level in the VTA by more excitatory (glutamatergic) and less inhibitory (GABAergic) inputs (Bayer and Pickel, 1991), which might further add to the particular properties of mesocortical cells. Interestingly, Garris and Wightman (1994) found that electrical stimulation of the medial forebrain bundle at physiological frequencies (10 – 20 Hz) produced the same (absolute) maximum overflow of DA in the mPFC as in the NAS and striatum, despite the great differences in the densities of the DA terminal fields in these different areas. Based on DA tissue contents alone, one would have expected the extracellular concentration of DA in the mPFC to be 90-fold less than in the NAS or striatum. The authors concluded that the unusually high DA concentrations in the mPFC are the results of a very high rate of DA release and the absence of an appropriately effective reuptake system. While the NAS and striatum were said to be ‘uptake dominated’ (i.e. extracellular DA levels are determined not so much be the rates of release but rather by the rates of reuptake), the mPFC was considered to be ‘release dominated’ (i.e. extracellular levels of DA are determined by the rates of release and not by the rates of reuptake). Due to the particular relative rates of release and reuptake, DA is thought to have a considerably longer extracellular half-life in the mPFC than in the NAS and striatum and is therefore able to diffuse over longer distances, possibly also to extrasynaptic sites (see discussion in Garris and Wightman, 1994). Thus, in the mPFC the physiological and anatomical framework would allow for DA ‘volume transmission’ (Herkenham, 1987; Vizi and Labos, 1991; Zoli et al., 1999), a feature thought not to exist for DA in the NAS or striatum (Garris and Wightman, 1994). Although too little is known so far about possible functional implications of such a non-synaptic transmission, it is clear that it adds an additional level of complexity to the analysis of the functioning of the mPFC.
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2.2.2. Responsi6ity to stress The mesocortical DA projection is particularly responsive to stress at low intensities that are not sufficient to activate the mesoaccumbal and mesostriatal projections to a comparable degree (Thierry et al., 1976a; Fadda et al., 1978; Lavielle et al., 1978; Tassin et al., 1980; Herman et al., 1982; Deutch et al., 1985, 1991a; Tam and Roth, 1985; Carlson et al., 1987b; Roth et al., 1988; Abercrombie et al., 1989; Mantz et al., 1989; Deutch and Roth, 1990; Pei et al., 1990; Bradberry et al., 1991; Kaneyuki et al., 1991; Cenci et al., 1992; Imperato et al., 1990c, 1991, 1992b; Sorg, 1992; Deutch, 1993; Kurata et al., 1993; Morrow et al., 1993; Sorg and Kalivas, 1993a,b; Inoue et al., 1994; Jedema and Moghaddam, 1994; Rasmusson et al., 1994; Feenstra and Botterblom, 1996; Nakahara and Nakamura, 1999), although it should be mentioned that a recent report shows that the mesoamygdaloid dopaminergic projection appears to be even more responsive to stress (Inglis and Moghaddam, 1999). A similar preferential activation of glutamatergic (Gilad et al., 1990; Moghaddam, 1993; Bagley and Moghaddam, 1997) and serotonergic (Kawahara et al., 1993; Yoshioka et al., 1995) transmission in the mPFC by stress has also been reported. Furthermore, noradrenaline release in the mPFC is also very sensitive to stress-activation (Hata et al., 1990; Rossetti et al., 1990; Gresch et al., 1994; Dalley and Stanford, 1995; Feenstra et al., 1995c, 1999; Finlay et al., 1995; Taber and Fibiger, 1997b). This, in turn, may also be relevant for the stress effects on DA given the potent mutual interactions between both transmitter systems. The mPFC is not only particularly sensitive to the effects of acute stress but also to the effects of chronic stress. Thus, compared to controls, rats preexposed to chronic cold, isolation stress or variable unpredictable stress showed a large increase in extracellular levels of both DA and NA and of DA metabolism in the mPFC but not in the NAS or striatum in response to an acute stressor (Blanc et al., 1980; Gresch et al., 1994; Cuadra et al., 1999). In addition to stress, DA in the mPFC is also increased by other salient environmental stimuli. For example, feeding can increase the release of DA (Hernandez and Hoebel, 1990; Feenstra and Botterblom, 1996), and as for stress, this effects appears to be more pronounced in the mPFC than in subcortical areas (Hernandez and Hoebel, 1988; Bassareo and Di Chiara, 1997). DA release in the mPFC is also particularly sensitive to exposure to novelty (Feenstra et al., 1995a; Feenstra and Botterblom, 1996; Rebec et al., 1997; see also Yee, 2000). 2.2.3. Responsi6ity to drugs 2.2.3.1. Dopaminergic drugs. DA uptake inhibitors generally have smaller effects on extracellular DA levels in
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the mPFC relative to the NAS or striatum (Hadfield and Nugent, 1983; Moghaddam and Bunney, 1989; Izenwasser et al., 1990; Elsworth et al., 1993; Wheeler et al., 1993; Cass and Gerhardt, 1995). Similarly, the stimulatory effects of D2 receptor antagonists on extracellular DA levels have been shown to be much more pronounced in the striatum as compared to the mPFC (Moghaddam and Bunney, 1990; Yamamoto et al., 1994). Consistent with the low levels of D2 (auto-) receptors in the mPFC (see section 2.1.2), it was found that systemic haloperidol induced a moderate increase in extracellular levels of DA in the striatum while having no significant effect in the mPFC. Also, while systemic amphetamine induced an increase in DA in both regions, this effect was by far greater in the striatum. On the other hand, co-administration of both drugs produced a considerably potentiated effect on extracellular DA levels in both structures, i.e. although haloperidol alone had virtually no effect on DA levels in the mPFC it significantly potentiated the DA-increasing effects of amphetamine (Pehek, 1999). This haloperidol-induced potentiation of amphetamine-stimulated DA efflux in striatum and mPFC appears to be mediated by different DA receptor populations, since the interactive effect of haloperidol and amphetamine in the striatum was blocked by the D1/D2 receptor agonist apomorphine, while this drug had no effect in the mPFC. On the other hand, the haloperidol–amphetamine interaction in the mPFC was significantly attenuated by the D2/D3 agonist quinpirole (Pehek, 1999). From these results it was concluded that there are D2-like (release-inhibiting) autoreceptors in the mPFC that are normally ‘silent’ under basal conditions and only come into play when extracellular levels of DA are considerably elevated. In other words, basal levels of DA are not autoreceptor-regulated in the mPFC while stimulated DA release is modulated via autoreceptor feedback (see also Wolf and Roth, 1987). The nature of this proposed type of autoreceptor is not clear, but the lack of effect of apomorphine, the effectiveness of quinpirole, and the findings of Gobert and collegues suggest that the effects might be mediated by D3 receptors (Gobert et al., 1995, 1996). The findings of Pehek (1999) are in good agreement with a number of other studies that have also shown a strong synergistic effect on extracellular DA levels in the striatum of a DA uptake inhibitor and a D2 receptor antagonist (Sharp et al., 1986b; Westerink et al., 1987; Gudelsky et al., 1992), and the results of Watanabe et al. (1989) show that both the effects of the uptake blocker and of the receptor antagonist are mediated locally within the striatum. In line with the diminished effects of DA uptake inhibitors on extracellular DA levels in the mPFC it has been found that the mPFC shows a smaller K+-evoked DA release relative to the striatum (Moghaddam et al.,
1990). In contrast to this, the anxiogenic beta-carboline FG 7142 produces a DA release in the mPFC but not in the striatum and NAS (Tam and Roth, 1985; Roth et al., 1988; Moghaddam et al., 1990; Bassareo et al., 1996) which may be related to the stress-inducing effects of this drug. A further functional distinction is that the mesocortical DA neurons are less sensitive to destruction by 6-OHDA than mesolimbic DA neurons, a fact that might be related to the higher relative density of noradrenergic innervation of the mPFC as compared to the NAS (Foote et al., 1983; Bjo¨rklund and Lindvall, 1986; Herve´ et al., 1986; Audet et al., 1988) since a high noradrenergic tonus may have neuroprotective effects in forebrain areas (Martel et al., 1999).
2.2.3.2. Glutamatergic drugs. A further difference between the cortical and subcortical dopaminergic systems lies in the way glutamate tonically and phasically regulates the basal release of DA in both regions at the cell body level in the VTA. Thus, basal NAS DA release is affected (i.e. reduced) to a much lesser degree than basal mPFC DA release by the injection of the NMDA receptor antagonist AP5 into the VTA (Karreman et al., 1996; Takahata and Moghaddam, 1998). Likewise, blockade of AMPA/kainate receptors in the VTA had no effect on DA release in the NAS (Chergui et al., 1993; Karreman et al., 1996; Westerink et al., 1996; Schilstro¨m et al., 1998) while it produced a clear reduction in basal extracellular DA levels in the mPFC (Takahata and Moghaddam, 1998). Furthermore, it has been demonstrated several times that systemic application of a non-competitive NMDA receptor antagonist (e.g. MK-801, PCP) or local administration of noncompetitive or competitive NMDA receptor antagonists is much more effective in increasing DA transmission in the mPFC than in the NAS or striatum (Bowers and Hoffman, 1984; Deutch et al., 1987; Rao et al., 1990a,b; Liljequist et al., 1991; Svensson et al., 1991; Bubser et al., 1992; Wedzony et al., 1993a,b; Nishijima et al., 1994, 1996; Verma and Moghaddam, 1996; Umino et al., 1998). These findings suggest that the basal activity of the two dopaminergic systems are under differential control of glutamate via NMDA receptors on the one hand and via AMPA/kainate receptors on the other hand. Interestingly, there is evidence to suggest that the DA-releasing effects of non-competitive NMDA receptor antagonists may be dependent upon their affinity for the PCP-binding site within the receptor-associated ion channel and the voltage-dependency of the binding. MK-801 and PCP, drugs that potently increase DA transmission in the mPFC, have a high affinity for the PCP-binding site and low voltage-dependency. On the other hand, memantine, a drug that has only moderate affinity for the PCP-binding site but strong voltage-dependency
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(see Parsons et al., 1993, 1996), has only very moderate effects on dopaminergic activity in the mPFC, both after acute and repeated (14 days) administration of a high dose (20 mg/kg) (Hesselink et al., 1999; see also Bubser et al., 1992). Furthermore, the finding of Nishijima et al. (1996) that TTX infusion into the mPFC completely blocked the increase in extracellular DA levels induced by systemic PCP suggests that the increase in mPFC DA produced by NMDA receptor antagonists depends upon an increase in impulse flow in the mesocortical DA projection. Rather different results were reported by Mathe´ et al. (1999). These authors found that basal levels of DA in mPFC and NAS and the MK-801 -induced increase in extracellular levels of DA in the NAS were both significantly reduced by intra-VTA infusion of tetrodotoxin (TTX). However, the MK-801 -induced increase in extracellular levels of DA in the mPFC was not significantly affected (Mathe´ et al., 1999). These findings suggest that while basal levels of DA in NAS and mPFC as well as the MK-801 -induced increase in NAS DA levels are dependent on impulse activity of the DA neurons, MK-801 increases extracellular levels of DA in the mPFC independently of impulse activity in DA neurons. This mechanism might involve local GABAergic interneurons (Yonezawa et al., 1998) and/or glutamate signalling via non-NMDA receptors (Moghaddam et al., 1997). These latter findings correspond well with electrophysiological data showing that MK-801 increases burst firing in neurons which presumably project to the NAS but reduces burst firing in neurons which presumably project to the mPFC (Murase et al., 1993b). When, despite the decrease in burst firing of DA neurons, a clear increase in extracellular levels of DA in the mPFC is observed after systemic MK-801 administration, this strongly suggests that MK-801 produces its effects independently of impulse flow. This implies that the regulation by glutamate (and possibly GABA) at the cell body level as well as at the nerve terminal level is quite different for mesocortical and mesoaccumbal DA neurons. This is in agreement with the findings of Kalivas et al. (1989) concerning the dichotomy at the level of the VTA for glutamate-induced stimulation of DA release/ metabolism in the two terminal regions. While glutamate injected into the VTA increased post-mortem levels of DA metabolites in both NAS and mPFC, injection of NMDA into the VTA selectively increased DA metabolism in the mPFC, and injection of kainate into the VTA selectively increased DA metabolism in the NAS. Also, coadministration of the competitive NMDA receptor antagonist CPP together with glutamate into the VTA selectively blocked the increase in DA metabolism in the mPFC but had no effects on DA metabolism in the NAS. Finally, intra-VTA injection of CPP also blocked the increase in DA metabolism in-
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duced by mild footshock stress (Kalivas et al., 1989). These data suggest that at the level of the VTA, glutamate-induced activation of dopaminergic activity in the mesolimbic and mesocortical system is mediated by different glutamate receptors. The stimulatory effect on mesocortical DA transmission appears to be mediated predominantly via NMDA receptors while the stimulatory effects on mesoaccumbal DA transmission are mediated via kainate (and possibly AMPA) receptors. It is intriguing to speculate if or how the impulse-dependent and impulse-independent effects on cortical DA release relate to the observed differences in the way mPFC DA release is regulated by NMDA receptors on the one hand and AMPA receptors on the other hand (Jedema and Moghaddam, 1996; Takahata and Moghaddam, 1998). Blockade of NMDA or AMPA receptors in the VTA as well as blockade of AMPA receptors in the mPFC reduced DA release in the mPFC (Takahata and Moghaddam, 1998). On the other hand, systemic competitive and non-competitive blockade of NMDA receptors, but not AMPA receptors, enhanced DA release or turnover in the mPFC (Hata et al., 1990; Wedzony et al., 1993b; Hondo et al., 1994; Nishijima et al., 1994; Bubser et al., 1995; Verma and Moghaddam, 1996). Conversely, activation of NMDA receptors reduced basal DA release when a relatively low dose of NMDA (0.1 mM) was infused into the mPFC (although a high dose of NMDA (1 mM) produced an increase in extracellular DA) (Feenstra et al., 1995b; Jedema and Moghaddam, 1996). Finally, infusion of AMPA or kainate into the mPFC produced a clear increase in extracellular levels of DA (Jedema and Moghaddam, 1996). This suggests that glutamate exerts a tonic excitatory influence on the dopaminergic system via AMPA and NMDA receptors in the VTA and via AMPA receptors in the mPFC and a tonic inhibitory influence via NMDA receptors in the mPFC (Takahata and Moghaddam, 1998). The inhibitory effects of NMDA receptor stimulation on prefrontal cortical DA release may be due to a preferential localization of NMDA receptors on GABAergic interneurons within the mPFC the activity of which has been shown to have an inhibitory influence on DA release (Santiago et al., 1993). That dopaminergic activity may be regulated differentially by AMPA receptors in the mPFC and in the NAS is also suggested by the findings of Bubser et al. (1995) who found that coadministration of the AMPA receptor antagonist GYKI 52466 blocked the increase in DA metabolism induced by the NMDA receptor antagonist MK-801 only in the NAS but not in the mPFC. The picture of glutamatergic regulation of DA release in the mPFC is further complicated by the fact that there may be differences between glutamatergic regulation of basal versus stimulus-evoked DA release. As in the case of regulation of basal DA release,
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blockade of AMPA and NMDA receptors in the VTA (Kalivas et al., 1989; Enrico et al., 1998) and of AMPA receptors in the mPFC reduced or blocked the DA release in response to handling stress. However, blockade of NMDA receptors in the mPFC, although increasing basal DA levels, had no effect on handling and tail pinch stress-induced DA release (Jedema and Moghaddam, 1994; Takahata and Moghaddam, 1998). Thus, prefrontal cortical NMDA receptors appear to be involved in the regulation of basal but not of stressevoked DA release. It remains to be determined, however, if this holds also true for the increase in DA release induced by other, non-stressful stimuli (Imperato et al., 1992b; Feenstra and Botterblom, 1996; Taber and Fibiger, 1997a,b).
2.2.3.3. Neuroleptics and antidepressants. The mesocortical DA projection was also found to be particularly responsive (in comparison to subcortical sites) to antidepressant drugs (Tanda et al., 1994; Gobert et al., 1997; Millan et al., 1997), the anticonvulsant mood stabilizers valproate and carbamazepine (Ichikawa and Meltzer, 1999), and ‘atypical’ neuroleptic drugs (Hand et al., 1987; Moghaddam and Bunney, 1990; Robertson and Fibiger, 1992; Moghaddam, 1994; Nomikos et al., 1994; Pehek and Yamamoto, 1994; Yamamoto and Cooperman, 1994; Schmidt and Fadayel, 1995; Deutch and Duman, 1996; Volonte´ et al., 1997; Li et al., 1998; Kuroki et al., 1999). In particular the preferential increase in prefrontal DA metabolism induced by ‘atypical’ neuroleptics has elicited a great deal of interest. It has been hypothesized that this effect may be related to the affinity of these drugs for the 5-HT2A receptor rather than for the D2 receptor (Leysen et al., 1993; Aghajanian and Marek, 1999) and that this preferential activation of prefrontal DA transmission may account for the improvement of negative symptoms of schizophrenia, which are thought to be related to prefrontal cortical dopaminergic hypofunction (Davis et al., 1991; Deutch et al., 1991b; Weinberger and Lipska, 1995; Tollefson and Sanger, 1997), brought about by these drugs. The suggestion that this effect of ‘atypical’ neuroleptic drugs may be due to their antagonistic effects at 5-HT2A receptors is consistent with the finding that local infusion of the 5-HT2A/c agonist DOI increases mPFC levels of GABA (Abi-Saab et al., 1998) and, in turn, clozapine clearly decreases extracellular levels of GABA in the mPFC (while haloperidol has only weak effects on mPFC GABA) (Bourdelais and Deutch, 1994). 5-HT2A receptors in the mPFC are located on interneurons as well as on pyramidal cells (Jakab and Goldman-Rakic, 1997; Willins et al., 1997), and interneurons are the target of serotonergic axon terminals (Smiley and Goldman-Rakic, 1996). Given these findings, it seems feasible that ‘atypical’ neuroleptics exert their effects on extracellular DA levels in the
mPFC by blocking serotonin-mediated GABA release at 5-HT2A receptors, thus relieving DA terminals from GABAergic inhibition (Santiago et al., 1993). An interesting anatomical finding of potential functional significance has recently been reported by Garzo´n et al. (1999).The authors showed that cholinergic axon terminals in the VTA make asymmetric (i.e. presumably excitatory) synapses only with cells that express no or only low levels of the plasmalemmal DA transporter (DAT). Since mesocortical DA neurons express lower levels of DAT than mesolimbic DA neurons (see section 2.2.1), this finding suggests that cholinergic input to the VTA modulates exclusively, or at least preferentially, the mesocortical system. Unfortunately, in the study of Garzo´n et al. (1999) the origin of the cholinergic afferents to the VTA were not determined, but there is evidence that the cholinergic innervation of the VTA originates in the pedunculopontine tegmental nucleus (PPTg) (Gould et al., 1989; Blaha et al., 1996; Yeomans and Baptista, 1997).
2.2.4. Role of the NA transporter for the reuptake of DA The NA transporter contributes importantly to the removal of DA from the extracellular space in the mPFC. DA has an even greater affinity for the NA transporter than NA itself, and the NA transporter has a denser and more widespread distribution than the DA transporter within the mPFC (Raiteri et al., 1977; Carboni et al., 1990; Izenwasser et al., 1990; Elsworth et al., 1993; Gehlert et al., 1993; Pozzi et al., 1994; Tanda et al., 1994; Bannon et al., 1995; Gresch et al., 1995a; Lee et al., 1996). The importance of NA transporter blockade by cocaine and amphetamine for the increase in extracellular levels of DA in the mPFC induced by these drugs has also been pointed out (Tanda et al., 1997). The relative importance of noradrenergic transmission (as compared to dopaminergic transmission) in the mPFC (as compared to NAS or striatum) is also suggested by the fact that the ratio of NA to DA concentration in the mPFC is 10 (Slopsema et al., 1982) while it is only 0.01 in the striatum (Palkovits, 1979). However, it is somewhat difficult to evaluate the importance of these mechanisms for the elimination of DA since the NA innervation of the mPFC is not homogeneous and appears to be relatively sparse in the deep layers of the prelimbic mPFC (Berger et al., 1976; Lindvall and Bjo¨rklund, 1984; Moore and Card, 1984; Cass and Gerhardt, 1995), that part of the mPFC which receives the densest DA innervation. Nevertheless, elevation of extracellular levels of NA by local application of desipramine significantly increased extracellular levels of DA and strongly potentiated stress-induced increases in extracellular DA levels in the mPFC (Tassin, 1992; Gresch et al., 1995b). These effects may be due either to a direct stimulatory action of NA on
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presynaptic DA release or to the fact that increased levels of extracellular NA will increase competition between DA and NA for available NA transporters, thus decreasing the relative proportion of DA taken up by the NA transporter (Raiteri et al., 1977; Carboni et al., 1990; Pozzi et al., 1994). Conversely, the release of NA appears to be regulated via D2 receptors within the mPFC (Rossetti et al., 1989). These potent interactions between DA and NA are a recurrent issue in 6-OHDA lesion studies of the mPFC, and a differential degree of NA depletion in addition to DA depletion induced by 6-OHDA injection may be an important factor when considering the variable results obtained in studies examining 6-OHDA lesion effects on behavior and neurotransmission within the mPFC and in subcortical areas (see Bunney and Aghajanian, 1976; Carter and Pycock, 1978, 1980; Tassin et al., 1979, 1986; see sections 3.2.2.1 and 4 for more details and references).
2.2.5. Transmitter co-localization A further distinguishing feature of mesocortical DA neurons lies in the nature of the cotransmitters which are co-localized with DA in these neurons. There is data to suggest that co-localization of neurotensin is a common feature of all mesocortical DA neurons while other dopaminergic projections co-localize neurotensin to varying but small degrees (Ho¨kfelt et al., 1984; Kalivas and Miller, 1984; Seroogy et al., 1987, 1988; Studler et al., 1988; Bean et al., 1989a). Since in the mPFC neurotensin is released under the same conditions of activity as DA (Bean et al., 1989b; Hertel et al., 1996) and since neurotensin has been shown to have potent physiological and behavioral effects in the mPFC (Rompre´ et al., 1998) it may well be the case that the release of neurotensin during activity of mesocortical neurons significantly contributes to the observed effects of this activity. DA neurons projecting to the NAS preferentially co-localize cholecystokinin (CCK). Thus, different physiological or behavioral effects of activity of mesocortical and mesolimbic projections might also be due to different effects of the co-localized transmitters in the respective target regions rather than or in addition to different effects of DA alone. 2.3. Interactions between dopamine and glutamate, and other transmitters, within the mesocorticolimbic circuit 2.3.1. Dopamine–glutamate – GABA interactions in the prefrontal cortex 2.3.1.1. Dopaminergic regulation of prefrontal pyramidal cells and interneurons. Although the action of DA on glutamatergic cells in the mPFC has received the most attention, considerable evidence also suggests that dopaminergic, serotonergic, glutamatergic and noradren-
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ergic inputs, along with intrinsic GABAergic transmission, make up a complex network of interactions among the different transmitter systems, most of which can influence each other mutually. It is beyond the scope of this review to give a detailed account of all the interactions of the different transmitter systems within the mPFC that have been described to date, but a number of exemplary studies will be summarized to demonstrate the complexity of the nature of interactions, with a focus on DA/glutamate/GABA interactions. The focus of interest in our present context are the effects of DA on the activity of the glutamatergic efferents of the mPFC (pyramidal cells). Many studies have addressed this issue, and the picture that emerges from these studies is complex. On the electrophysiological level, one cannot simply state that DA in the mPFC has this or that effect on pyramidal neurons, but the effects of DA depend on a whole number of factors that are important in determining the effects of DA. The most general picture that emerges from a number of studies is that DA or DA agonists applied directly into the mPFC or stimulation of DA release by means of chemical or electrical activation of the VTA generally inhibits the activity of pyramidal cells in the mPFC (Bunney and Aghajanian, 1976; Mora et al., 1976; Reader et al., 1979; Bernardi et al., 1982; Ferron et al., 1984; Rolls et al., 1984; Sawaguchi and Matsumura, 1985; Thierry et al., 1986; Gratton et al., 1987; Jahkel et al., 1987; Peterson et al., 1987, 1990; Mantz et al., 1988; Thierry et al., 1986, 1988; Sesack and Bunney, 1989; Parfitt et al., 1990; Qiao et al., 1990; Yang and Mogenson, 1990; Godbout et al., 1991; Karreman and Moghaddam, 1996; Gulledge and Jaffe, 1998; Gobbi and Janiri, 1999). Whether DA inhibition of pyramidal cells is a direct or an indirect effect is not entirely clear but evidence exists that the inhibitory effect of DA on pyramidal cells may involve both an excitation of GABAergic interneurons by DA, which would in turn inhibit the pyramidal cells (Mercuri et al., 1985; PenitSoria et al., 1987; Re´taux et al., 1991a; Pirot et al., 1992; Grobin and Deutch, 1998) and a direct inhibitory action of DA on pyramidal cells (Geijo-Barrientos and Pastore, 1995; Gulledge and Jaffe, 1998). However, the effects of DA on the postsynaptic cell can depend on the type of cell and on the type of DA receptor activated. While the effects of DA on GABAergic cells appear to be mediated primarily by the D2 receptor (Re´taux et al., 1991a; Grobin and Deutch, 1998), it is not clear yet which receptor type mediates the effects of DA on pyramidal cells, and both receptor types (D1 and D2) have been implicated (Sesack and Bunney, 1988; Parfitt et al., 1990; Godbout et al., 1991; Pirot et al., 1992; Law-Tho et al., 1994; Gulledge and Jaffe, 1998). It should be noted here, however, there is some controversy about the exact nature of the D2 receptor
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type thought to be involved in these mechanisms since the effect of endogenous DA is not blocked by haloperidol and is also not mimicked by the D2 agonist quinpirole (Sesack and Bunney, 1988; Godbout et al., 1991). This suggests that an additional, pharmacologically not yet well characterized D2-type receptor may exist in the mPFC. The picture is further complicated by the fact that several different, morphologically, neurochemically and physiologically distinct sub-populations of pyramidal cells and interneurons exist (Grace and Llinas, 1984; Kawaguchi and Kubota, 1993, 1996; Kawaguchi, 1993, 1995; Yang et al., 1996a,b; Gabbott and Bacon, 1995, 1996a,b, 1997; Gabbott et al., 1997) which may also respond differentially to dopaminergic input (Deutch and Duman, 1996). In addition, the effects of DA also depend on whether the postsynaptic cell is in a rested or in an active (depolarized) state (Hernandez-Lopez et al., 1997; Stern et al., 1997; Ce´peda et al., 1998), on whether proximal or distal dendrites of the postsynaptic cell are activated (Yang and Seamans, 1996) and on whether other (glutamatergic, GABAergic, noradrenergic, serotonergic, cholinergic) inputs to the postsynaptic cell are also active (Yang and Mogenson, 1990; Beauregard and Ferron, 1991; Ce´peda et al., 1992; Surmeier and Kitai, 1993, 1997; Law-Tho et al., 1995; see Yang et al., 1999, for a recent comprehensive review of electrophysiological actions of DA in the mPFC). In this context, it is also interesting to note that the inhibitory effects of DA were mainly observed in in vivo preparations (see references above), while in vitro preparations have generally shown a depolarizing effect of DA on mPFC neurons (Penit-Soria et al., 1987; Yano et al., 1989, 1991; Law-Tho et al., 1994; GeijoBarrientos and Pastore, 1995; Shi et al., 1997; Ceci et al., 1999). Finally, pyramidal cell responses to NMDA receptor stimulation depends on the concentration of DA present at the synapse. Zheng et al. (1999) found that low concentrations of DA enhanced current responses to NMDA application while high concentrations reduced these responses. Interestingly, these differential effects were specifically related to D1 and D2 receptors in that the activating effect of DA was mediated by the D1 receptor and the inhibitory effect of DA was mediated by the D2 receptor. As Yang and Seamans (1996), p.1932) put it: ‘‘… the action of DA on pyramidal PFC neurons is neither ‘excitatory’ nor ‘inhibitory’ but depends on the foci, timing, and strength of synaptic inputs, as well as on the membrane potential range at which the PFC neuron is operating.’’ As in the striatum (Braun and Chase, 1986; Carlson et al., 1987a; Walters et al., 1987; White, 1987), there seems to exist a synergism between D1 and D2 receptor-mediated events such that activation of the one receptor type can enhance the responses to activation of the other receptor type, or that activation of one recep-
tor type even is necessary for the expression of responses to stimulation of the other receptor type (Sesack and Bunney, 1988; Re´taux et al., 1991b).
2.3.1.2. Glutamatergic regulation of prefrontal dopaminergic afferents. It was mentioned above that stress increases the release of DA and glutamate preferentially in the mPFC compared to other basal ganglia structures. However, it is not quite clear to date how these two phenomena relate to each other. Generally, stimulation of dopaminergic activity (release, metabolism) in the mPFC after local and peripheral administration of non-competitive as well as competitive NMDA receptor antagonists has been reported (Hata et al., 1990; Tanii et al., 1990; Wedzony et al., 1993b; Hondo et al., 1994; Nishijima et al., 1994; Kashiwa et al., 1995; Wheeler et al., 1995; Jedema and Moghaddam, 1996; Yonezawa et al., 1998). However, ionotropic glutamate receptors have not yet been convincingly shown to be present on dopaminergic terminals in the mPFC (Fink et al., 1992; Petralia and Wenthold, 1992; Petralia et al., 1994a,b; DeBiasi et al., 1996), and it may be that glutamate influences dopaminergic transmission in the mPFC predominantly via ionotropic receptors located on GABAergic terminals and/or dendrites (Nishijima et al., 1994; Feenstra et al., 1995b; DeBiasi et al., 1996). In this respect, the situation appears to be different in the NAS, since there metabotropic rather than ionotropic glutamate receptors regulate basal and stimulated DA release (Taber and Fibiger, 1995; Feenstra et al., 1998) although some evidence for the existence of NMDA receptors on dopaminergic terminals in the NAS also exists (French et al., 1985). The findings for the effects of NMDA receptor agonists have been more inconsistent. Increases (Cheramy et al., 1986; Jhamandas and Marien, 1987; Jones et al., 1993; Feenstra et al., 1995b), decreases (Cheramy et al., 1986; Feenstra et al., 1995b) and no effects (Jedema and Moghaddam, 1996; Yonezawa et al., 1998) on dopaminergic activity of NMDA receptor agonists have been reported. The dose-dependent effects found by Feenstra et al. (1995b), Cheramy et al. (1986) suggest that these discrepant findings may be, at least in part, be explained by the use of different doses of the agonist. The findings of Jones et al. (1987, 1988, 1993), Feenstra et al., (1993) that electrical or chemical stimulation of excitatory afferents to the mPFC increases dopaminergic activity in the mPFC, however, suggests that physiologically released glutamate in the mPFC may indeed stimulate DA release at the terminal level. The effects of AMPA/kainate receptor blockade or stimulation on extracellular DA levels in the mPFC have not been studied yet to the same extent, but the available data suggest that DA release is stimulated by agonists of these receptors (Jones et al., 1993; Jedema and Moghaddam, 1996). Furthermore, blockade of
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AMPA (and possibly NMDA) receptors in the mPFC blocked the local stress-induced increase in DA release (Jedema and Moghaddam, 1994). The most straightforward explanation for these findings would be that activation of glutamate transmission in the mPFC by stress would — via presynaptically located AMPA or NMDA receptors — increase the release of DA within the mPFC. Nevertheless, alternative explanations also exist. For example, activation of glutamatergic transmission in the mPFC by stress or experimental manipulations could lead to a stronger activation of the glutamatergic projections from the mPFC to the VTA (directly or via the PPTg), which in turn could stimulate mesocortical DA neurons in the VTA to release more DA into the mPFC. A further possibility is that the increased release of glutamate in the mPFC induced by stress is not involved in the concurrent increase in DA release, neither directly nor indirectly. It could be that DA release is stimulated by activation of dopaminergic cells at the level of the VTA by excitatory input unrelated to the mPFC. Since the VTA also receives excitatory input from the amygdala, the hippocampus and the PPTg, glutamatergic input to the VTA from these sources could also lead to enhanced DA release in the mPFC (Deutch and Roth, 1990; Kalivas et al., 1989; Kalivas, 1993; Morrow et al., 1993). The effects of endogenous glutamate on extracellular levels of DA and its metabolites, and of GABA have been studied by Del Arco and Mora (1999). These authors found that increasing extracellular levels of glutamate in the mPFC by local infusion of the glutamate uptake inhibitor PDC increases GABA levels, does not affect DA levels and decreases levels of the DA metabolites DOPAC and HVA. The increase in extracellular GABA was blocked by the AMPA/kainate receptor antagonist DNQX but was not affected by the competitive NMDA receptor antagonist CPP. Conversely, the PDC-induced decrease in extracellular DA metabolites was blocked by CPP but was not affected by DNQX. These results suggest that endogenous glutamate increases GABAergic activity in the mPFC primarily via AMPA/kainate receptors while it decreases DA metabolism primarily by acting on NMDA receptors. This also implies that the reduction of dopaminergic activity in the mPFC by glutamate is not secondary to an increase in inhibitory GABAergic transmission. These data are not entirely consistent with the results of Yonezawa et al. (1998) who found that NMDA receptor antagonists decreased extracellular levels of GABA in the mPFC while, however, NMDA failed to increase extracellular GABA. Taken together, these results would imply that basal extracellular levels of GABA are (positively) regulated via NMDA receptors while glutamate-induced stimulation of GABA release is mediated via AMPA/kainate receptors.
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Finally, GABA is also positively modulated by DA (presumably predominantly via the D2 receptor) (Grobin and Deutch, 1998) and in turn, GABAergic transmission modulates mPFC DA release (presumably via both GABA-A and GABA-B receptors) (Santiago et al., 1993).
2.3.2. Dopamine–glutamate–GABA–acetylcholine interactions in the VTA 2.3.2.1. Glutamatergic regulation of VTA dopamine neurons. Using ligand binding, in situ hybridization and immunohistochemical methods, relatively high levels of GABA-A and GABA-B receptors, and of NMDA and non-NMDA glutamate receptors have been shown to be present in midbrain dopaminergic neurons (Albin et al., 1992; Petralia and Wenthold, 1992; Martin et al., 1993; Sato et al., 1993; Standaert et al., 1993, 1994; Laurie and Seeburg, 1994; Petralia et al., 1994a,b; Lu et al., 1999a,b). These receptors are likely to be the basis of the electrophysiological and neurochemical effects of locally or systemically applied glutamate and GABA agonists and antagonists. In a series of studies, Westerink and collegues (Santiago and Westerink, 1991, 1992; Westerink et al., 1992, 1996, 1998) carried out a pharmacological analysis of the regulation of the major dopaminergic projections (nigrostriatal, mesolimbic, and mesocortical) at the level of the VTA. These studies revealed similarities as well as differences between the different projections in their response to pharmacological manipulation in the VTA. With respect to GABAergic modulation it was found, for example, that while intra-VTA application of the GABA-A agonist muscimol reduced extracellular levels of DA in both the NAS and the mPFC it actually increased extracellular DA in the striatum. On the other hand, a comparable increase in DA was seen in all 3 terminal areas after intra-VTA administration of the GABA-A antagonist bicuculine. Intra-VTA infusion of the GABA-B antagonist baclofen moderately reduced extracellular levels of DA in the mPFC but strongly reduced DA in the NAS and striatum. With respect to glutamatergic modulation it was found that NMDA infusion into the VTA produced a pronounced but short-lasting increase in extracellular DA in the mPFC, but a weaker and more prolonged DA increase in the NAS and striatum. On the other hand, infusion of kainate into the VTA produced a moderate and transient increase in DA in the mPFC and NAS while it produced a small but delayed and long-lasting increase in DA in the striatum. These data suggest that different populations of dopaminergic neurons are under complex and differential control of GABAergic and glutamatergic (as well as dopaminergic and cholinergic; see references below) inputs.
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The effects of glutamate antagonists as well as agonists on DA cell activity can be quite different in in vitro versus in vivo preparations and also in anesthetized versus awake animals. The general picture that has emerged from numerous and partly controversial papers is that the results can be grouped into three broad categories according to the methods used. (1) Using the slice preparation, where naturally occurring bursts are absent (Grace and Bunney, 1983, 1984a,b; Sanghera et al., 1984; Grace and Onn, 1989) NMDA and AMPA/kainate receptor antagonists had no consistent effects of the electrophysiological activity of VTA cells (Wang and French, 1993a). On the other hand, glutamate, NMDA, AMPA and kainate all increased firing rate without inducing burst activity (Seutin et al., 1990; Wang and French, 1993a,b). The effect of NMDA was found to be biphasic in that low to intermediate doses of NMDA had clear stimulatory effects on the firing rate while high doses reduced firing rate, possibly due to depolarization inactivation. These alterations in firing rate closely correlated with DA release in the NAS when the VTA was perfused with the same doses of NMDA via a microdialysis probe (Wang et al., 1994). It should be mentioned that there is one report showing that bursting can be induced in the slice preparation by application of NMDA (but not kainate or quisqualate) (Johnson et al., 1992). However, this effect appears to be due to the particular procedures and methods employed in that study so that these results cannot necessarily be compared to the majority of the other slice studies (see references for details). Interestingly, Wang and French (1995) found, using intracellular recordings, that AMPA, kainate and NMDA (in this potency rank order) also depolarized non-DA neurons in the VTA. (2) Using direct local drug application onto DA cells (most commonly by microiontophoresis) in the anesthesized whole animal, no effects were found for MK-801 (Zhang et al., 1992) and only relatively weak, inhibitory effects were observed for PCP (Freeman and Bunney, 1984; French, 1986a), while the glutamate receptor antagonist kynurenic acid reduced spontaneous burst firing activity (Charle´ty et al., 1991). On the other hand, iontophoretic administration of the receptor agonists AMPA, kainate, glutamate and NMDA (in this potency rank order) produced an increase in cell firing and in burst activity in dopaminergic as well as nondopaminergic cells, at least in the substantia nigra (Zhang et al., 1994). As mentioned above, glutamate agonists increase firing rate but do not induce burst firing in VTA slice preparations. Based on the available data it is difficult to determine whether the induction of burst activity in this study is due to the fact that the experiments were done in whole animals, as opposed to the slice, or whether this observation represents a difference between VTA and substantia nigra cells. (3) Using systemic drug application in whole
animals, PCP increased average firing rate at low to intermediate doses and decreased firing rate at very high doses (Freeman and Bunney, 1984; Pawlowski et al., 1990; French et al., 1991; French, 1986a, 1992). MK-801 and TCP, but interestingly not the competitive NMDA receptor antagonists CGS 19755, NPC 12626 and CPP, also increased average firing rate and in some cases also burst activity (French et al., 1991, 1993; French, 1992; Zhang et al., 1992; Murase et al., 1993b). In fact, the ability of non-competitive NMDA receptor antagonists to increase firing in DA neurons is positively correlated to their channel-blocking potency (French and Ceci, 1990), and the stimulatory effect of low to moderate doses of PCP can be blocked or attenuated by coadministration of competitive NMDA receptor antagonists, suggesting that the stimulatory effect of PCP (at least at low to moderate doses) is largely due to its channel-blocking properties (‘use-dependency’) (French, 1992). Interestingly, Zhang et al. (1993) found that MK-801 reduced the firing rate of nondopaminergic VTA neurons. Based on this, it is tempting to speculate that the stimulatory effects of systemic NMDA receptor antagonists on DA cell firing are at least partly due to a indirect, disinhibitory mechanism at the level of the VTA, such that PCP, MK-801 and related drugs block the activity of GABAergic interneurons in the VTA, thus relieving DA neurons from GABAergic inhibition. This ‘local-loop’ mechanism is consistent with the finding that hemitransections that separate the forebrain from the midbrain attenuate but do not completely block the excitatory effects of systemic MK-801 on DA neurons (Zhang et al., 1992). It is also consistent with the above-mentioned demonstration that non-DA neurons in the VTA are depolarized by AMPA, kainate and NMDA (Wang and French, 1995). The effects of glutamatergic drugs on the firing pattern of dopaminergic cells in general and on the burst activity of these cells in particular are of great interest because of the relationship between cell firing pattern and DA release in the terminal regions. Most importantly, firing rate and DA release are non-linearly related in that burst activity is particularly effective in releasing DA at high rates (Gonon and Buda, 1985; Gonon, 1988; Chergui et al., 1994a). The marked lack of effect of competitive NMDA receptor antagonists on the electrophysiology despite their marked overall behavioral effects is a phenomenon that has not been explained satisfactorily to date, but it implies that blockade of the NMDA receptor-associated ion channel has other or additional ionic, and therefore in effect electrophysiological, consequences than blockade of the glutamate binding site. Taken together, these results suggest that glutamatergic afferents to the VTA are crucial for the generation of burst activity. This suggestion is supported by the
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observation that stimulation of structures that send glutamatergic projections to the VTA/SN also induces burst firing in midbrain DA neurons (PFC: Gariano and Groves, 1988; STN: Smith and Grace, 1992; Chergui et al., 1994b; PPTg: Di Loreto et al., 1992; Lokwan et al., 1999; see also Kitai et al., 1999). At the DA cell level in the VTA NMDA receptor antagonists reduce the activity of these cells but in the intact animal this inhibitory effect is overridden by the activation of potent excitatory inputs from other brain areas to the VTA and/or by local disinhibitory mechanisms that result in a net increase in DA cell activity and increased bursting. The fact that systemically administered MK801 does not block these excitatory inputs onto DA cells may be nicely explained by the finding of Mathe´ et al. (1998) who suggested that the stimulatory, glutamatergic effect of MK-801 is mediated via AMPA receptors at the level of the VTA, which would be unaffected by the systemically administered MK-801. The influence of the mPFC on dopaminergic neurotransmission is particularly obvious from studies in which the effects of activation or inactivation of the mPFC on the activity of DA neurons in the VTA were examined. Chemical or electrical stimulation of the mPFC increases the firing rate and changes the firing pattern of DA neurons in the VTA (Thierry et al., 1979; Gariano and Groves, 1988; Chergui et al., 1993, 1994b; Murase et al., 1993a). In fact, electrical stimulation of the mPFC at the appropriate parameters produces burst firing in DA neurons that is virtually indistinguishable from naturally occurring burst events (Overton et al., 1996; Overton and Clark, 1997; Tong et al., 1996a,b, 1998) and, as mentioned above, glutamatergic input to the VTA appears to be essential for the induction of bursts since spontaneous burst activity does not occur in slice preparations (Pinnock, 1983; Grace and Bunney, 1984a,b; Sanghera et al., 1984; Silva and Bunney, 1988; Grace and Onn, 1989; Seutin et al., 1990; Suaud-Chagny et al., 1992). On the other hand, temporary inactivation of the mPFC reduces firing rate and the occurrence of burst firing in DA neurons (Svensson and Tung, 1989; Murase et al., 1993a), and systemic and local administration of glutamate (in particular NMDA) receptor antagonists also reduces the occurrence of burst activity (Grenhoff et al., 1988; Charle´ty et al., 1991; Overton and Clark, 1992; Chergui et al., 1993). Furthermore, ibotenic acid lesions of the mPFC decrease the number of spontaneously active cells in the VTA (Shim et al., 1996; note, however, that in this study the mPFC lesions produced an increase in firing rate in SN dopaminergic cells, suggesting that mPFC input to different DA neuron populations in the midbrain does not have uniform effects on the activity of these populations). The increase in burst firing in VTA neurons as a result of mPFC stimulation probably directly accounts for the increase in DA release in the
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NAS observed during mPFC stimulation (Taber and Fibiger, 1993, 1995; Nissbrandt et al., 1994; Taber et al., 1995; You et al., 1998). This effect is mediated by the activation of NMDA — but not AMPA — receptors in the VTA (Overton and Clark, 1992; Chergui et al., 1993; Taber et al., 1995; Karreman and Moghaddam, 1996; Karreman et al., 1996; Tong et al., 1996a). It has been mentioned above that the effects of DA in the mPFC not only depend on the type of postsynaptic cell upon which it acts but also on the state (i.e. level of membrane de- or hyperpolarization due to the activity of other inputs) of that postsynaptic cell. The findings of Kiyatkin and Rebec (1998) suggest that the same may also be true for the effects of glutamate (and GABA) upon dopaminergic cells in the VTA. They found that presumed dopaminergic neurons responded with different degrees of monophasic excitation, biphasic excitation-inhibition, or weak monophasic inhibition to the same amount of iontophoretically applied glutamate current depending on their activity state prior to glutamate application or on the behavioral state of the animal (which in turn presumably influenced the activity state of the DA neurons). Thus, as it is too simplistic to state that DA ‘simply’ inhibits postsynaptic cells in the mPFC, it is also probably inappropriate to state that glutamate ‘simply’ excites postsynaptic cells in the VTA. Difficult to reconcile with the evidence reviewed above is the finding by Harden et al. (1998) that 6-OHDA lesions of the mPFC also decreased activity of DA neurons in the VTA (slower mean firing rate, decrease in relative burst activity, but no effect on the number of spontaneously active cells). This effect cannot be explained by the mechanisms outlined above according to which DA inhibits mPFC glutamatergic efferents to the VTA which stimulate DA neurons. It could, however, be easily explained if the predominant targets of mPFC glutamatergic input to the VTA were indeed GABAergic interneurons which inhibit DA neurons. An alternative explanation would involve the mPFC glutamatergic efferents to the NAS which stimulate GABAergic spiny neurons which in turn project to the VTA and inhibit DA neurons. Whichever mechanism turns out to be correct, neither of them can be reconciled with the explanations for effects of increased DA in the mPFC or electrical stimulation of the mPFC, both of which postulate a direct or indirect (i.e. longloop) excitatory influence of glutamatergic mPFC efferents on VTA DA neurons. Interestingly, very similar 6-OHDA lesions and experimental conditions like those of Harden et al. (1998), i.e. lesions that reduced the activity of dopaminergic neurons, did not have significant effects on basal extracellular levels of DA in the NAS but did augment stress-induced DA release in the NAS (King et al., 1997). This implies that compensa-
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tory mechanisms in the NAS were induced by mPFC DA depletion to maintain extracellular DA concentration at pre-lesion levels despite reduced DA cell activity. These mechanisms might include a decreased sensitivity of DA autoreceptors or a decreased activity of DA reuptake transporters in the NAS. These compensatory mechanisms might also explain the increased DA response to stress (see Harden et al., 1998 for further discussion). Based on anatomical and electrophysiological grounds it appears likely that the stimulatory effect of mPFC stimulation on DA cell activity (and probably also the influence of the mPFC under natural physiological conditions) is in large part not mediated by a direct glutamatergic input to VTA DA cells from the mPFC (although a direct effect may also be possible; see McCormick et al., 1985; Overton and Clark, 1997). Glutamatergic afferents of the VTA originating from the mPFC synapse predominantly on non-DA cells (Sesack and Pickel, 1992) and the latencies of the DA neuron response to mPFC stimulation are too long for a monosynaptic connection (Tong et al., 1996b, 1998). Thus, it seems more likely that the effects of mPFC stimulation on DA cell firing are mediated via a oligoor polysynaptic loop which possibly includes the PPTg, which receives cortical input (Moon-Edley and Graybiel, 1983), has a direct, excitatory projection to the VTA (Phillipson, 1979; Jackson and Crossman, 1983; Scarnati et al., 1986) the transmitters of which appear to be glutamate and acetylcholine (Scarnati et al., 1986; Clements and Grant, 1990; Futami et al., 1995; Takakusaki et al., 1996; Grofova and Zhou, 1998). The impact of prefrontal glutamatergic input to non-DA cells in the VTA on DA cell activity has been examined by Tong et al. (1998). From their data the authors concluded that the glutamatergic input to non-DA cells in the VTA is primarily monosynaptic and does not affect the immediate firing behavior or the properties of individual action potentials of dopaminergic cells on a short time-scale (i.e. phasically). Rather, this input appeared to influence DA cell activity on a longer timescale (i.e. tonically) (Overton and Clark, 1997).
2.3.2.2. Cholinergic regulation of VTA dopamine neurons. When considering the finding that the PPTg can also provide excitatory input for midbrain DA neurons it should be kept in mind that this input may not exclusively be mediated by glutamate but may also be carried by acetylcholine. In fact, acetylcholine activation of both, nicotinic and muscarinic receptors on DA neurons causes depolarization and increases in firing rate and bursting (Calabresi et al., 1989; Gronier and Rasmussen, 1998; Sorenson et al., 1998). Thus, although acetylcholine may not be the main driving force of DA neurons and may also not be the ultimate agent responsible for the induction of burst activity, it may
nevertheless facilitate the induction of bursts by other excitatory inputs. That acetylcholine does not have a trivial action in the midbrain is exemplified by the finding that acetylcholine apparently reduces glutamate release via presynaptic muscarinic receptors (Grillner et al., 1999) and increases GABA release via presynaptic muscarinic receptors on striatonigral terminals (Kayadjanian et al., 1994). Thus, in addition to its direct stimulatory actions on DA neurons, acetycholine also has an indirect inhibitory effect, and the net effect of acetylcholine released in the VTA/SN on the activity of DA neurons will depend on a complex interplay with dopaminergic, glutamatergic and GABAergic elements (see Kitai et al., 1999). As mentioned in section 2.2.3.3, cholinergic axon terminals in the VTA appear to target predominantly mesocortical DA neurons (Garzo´n et al., 1999). This observation might be important for the well known, but as yet unexplained, anti-Parkinsonian effects of anticholinergic drugs in animal models and in patients with Parkinson’s disease (PD). If cholinergic input to the VTA is indeed predominantly activating mesocortical DA neurons, then anticholinergic drugs should predominantly reduce activity of those cells. This would reduce inhibitory dopaminergic input to pyramidal cells in the mPFC, thus enhancing activity of prefrontal cortical excitatory efferents to the VTA, which would in turn lead to enhanced activity of the remaining dopaminergic neurons projecting to the NAS, and thus produce an anti-Parkinsonian effect. This scenario is of course highly speculative and is difficult to reconcile with several demonstrations that nicotinic as well as muscarinic agonists activate dopaminergic cells in the VTA, and produce locomotion and reward (Grenhoff et al., 1986; Mereu et al., 1987; Calabresi et al., 1989; Corrigall and Coen, 1989; Lacey et al., 1990; Museo and Wise, 1990, 1994a,b, 1995; Corrigall et al., 1994; Nisell et al., 1994a,b; Panagis et al., 1996; Pidoplichko et al., 1997; Yeomans and Baptista, 1997; Gronier and Rasmussen, 1998). Nicotinic as well as muscarinic acetylcholine receptors have been shown to be located on dopaminergic cells in the VTA (Clarke and Pert, 1985; Goldner et al., 1997), but to our knowledge it has not been determined whether these receptors are located on mesolimbic or on mesocortical DA neurons. If one assumes that receptors are mainly associated with synaptic contacts, the findings of Garzo´n et al. (1999) would imply that these receptors are located on mesocortical neurons. However, if cholinergic receptors were more evenly distributed on both mesocortical and mesolimbic neuron populations, then it could be the case that in the intact animal the stimulatory cholinergic input on mesolimbic neurons ‘outweighs’ the effect on mesocortical neurons (which would, via increased inhibitory input to the mPFC, decrease glutamatergic excitatory input to the VTA and would thus act to
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decrease NAS DA release), such that overall cholinergic stimulation of the VTA would result in increased NAS DA release, locomotion and reward. There is evidence that at least during the early stages of PD, in addition to the degeneration of the nigrostriatal projection, mesolimbic DA neurons are affected to a greater degree than mesocortical DA neurons (Forno, 1990). Thus, it could be that under pathological conditions behavioral and neurochemical effects of cholinergic drugs in the VTA are no longer primarily mediated via mesolimbic DA neurons but rather by mesocortical DA neurons. If this was indeed the case, then in the Parkinsonian brain anticholinergic drugs would act predominantly on mesocortical neurons, leading to effects as outlined above. Another mechanism by which nicotine could activate mesoaccumbal DA neurons despite the apparent relative scarcity of cholinergic input to these cells is via presynaptic facilitation of glutamate release in the VTA from terminals of mPFC afferents (see Vidal, 1994; Wonnacott et al., 1996; Schilstro¨m et al., 1998). Clearly, more work needs to be done to resolve these issues. Amongst other things, it would be interesting to determine how anticholinergics affect dopaminergic transmission in the mPFC and glutamatergic transmission in the VTA in intact and in 6-OHDA lesioned animals, or the exact relationship of cholinergic terminals with dopaminergic cells in the SN, since the nigrostriatal projection is also, and even more importantly involved in Parkinson’s disease.
2.3.2.3. The role of VTA GABAergic neurons. Electrical and chemical stimulation of the mPFC induces release of glutamate, DA and CCK in the striatum and NAS (Taber and Fibiger, 1993, 1995; Taber et al., 1995; Karreman and Moghaddam, 1996; Lada et al., 1998; You et al., 1998). The source of glutamate and CCK most likely are the direct projections originating in the mPFC (Godukhin et al., 1980; Young and Bradford, 1986; Palmer et al., 1989; Perschak and Cuenod, 1990; Lada et al., 1998; You et al., 1998). The release of glutamate is regulated by metabotropic glutamate receptors located presynaptically on glutamatergic terminals, although the mechanisms of this presynaptic regulation and the precise involvement of the different mGluR subtypes is not yet entirely clear (Lovinger et al., 1993; Taber and Fibiger, 1995; Tyler and Lovinger, 1995; Lada et al., 1998). A closer look at the anatomical organization of the circuits involved may resolve the apparent paradox that stimulation of the mPFC induces DA release in the NAS despite the fact that glutamatergic afferents to the VTA have been shown to synapse predominantly on non-dopaminergic cells (i.e. presumably GABAergic neurons) in the VTA (Sesack and Pickel, 1992; Wang and French, 1995). Activation of these GABAergic cells
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would be expected to have an inhibitory effect on dopaminergic cells, which is incompatible with the observed increase in DA release in the NAS. However, given that a GABAergic projection from the VTA to the NAS/striatum also exists (van Bockstaele and Pickel, 1995) which terminates predominately on cholinergic interneurons (Pickel and Chan, 1990), it might be that the glutamatergic prefrontal cortical input to the VTA terminates predominantly not on GABAergic interneurons that would in turn inhibit dopaminergic neurons but rather on those GABAergic cells that project to subcortical targets. This would inhibit the cholinergic interneurons in NAS/striatum, thus decreasing excitatory cholinergic input to medium spiny neurons. In addition to this ‘indirect’ mechanism the ‘direct’ mPFC-VTA-NAS pathway would be responsible for the DA release observed in the NAS after mPFC stimulation. This outlined scenario may also explain why the rewarding effects of mPFC self-stimulation appear to be mediated via glutamatergic transmission in the VTA yet seem to be relatively independent of dopaminergic mechanisms (see section 3.1.3). Yet another scenario is possible. Stimulation of the mPFC is likely to result in activation of the glutamatergic cortico-accumbal projection (Tzschentke et al., 1997; You et al., 1998). Glutamate released in the NAS would activate GABAergic spiny neurons. Since these neurons project to the ventral pallidum, but also to the VTA, mPFC stimulation would ultimately lead to increased GABA release in the VTA. Assuming that GABA would predominantly act on GABAergic interneurons, this would relieve DA neurons from GABAergic inhibition, thus leading to enhanced DA release in the NAS. Of course, this mechanism is speculative and awaits experimental testing. It is also not consistent with the observation that the effects of mPFC stimulation on NAS DA release can be blocked by intra-VTA blockade of glutamate receptors (see references above), since this mechanism would require the action of GABA rather than glutamate in the VTA.
2.3.3. Dopamine–glutamate–GABA interactions in the NAS 2.3.3.1. Glutamatergic regulation of accumbal spiny neurons. When discussing the possible relevance of the corticoaccumbal/corticostriatal projection for behavioral output it should be kept in mind that this may crucially depend upon whether this glutamatergic input targets NMDA- or AMPA receptors. As outlined below, NMDA receptor blockade at the level of the NAS/striatum clearly has stimulatory effects on behavior. By implication (Schmidt and Bury, 1988) activation of NMDA receptors in the NAS/striatum should reduce behavioral output. Interestingly, the effect medi-
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ated via AMPA receptors appears to be quite the opposite to that of NMDA receptors. Thus, moderate doses of AMPA injected into the NAS or striatum produce behavioral activation (Boldry et al., 1993; Svensson et al., 1994b). Conversely, in studies using systemic injections of the AMPA antagonists NBQX or GYKI52466 it was found that although these drugs had only very minor effects on spontaneous behavior (Danysz et al., 1994; Bubser et al., 1995), they did not have anti-cataleptic effects in DA-antagonist induced catalepsy (Papa et al., 1993; Zadow and Schmidt, 1994) (in contrast to NMDA receptor antagonists) and even increased raclopride-induced catalepsy (Papa et al., 1993), and attenuated the locomotor stimulant and anticataleptic effects of MK-801 (Hauber and Andersen, 1993; Bubser et al., 1995).
2.3.3.2. Glutamatergic regulation of accumbal dopaminergic afferents. As mentioned above, the mPFC importantly influences dopaminergic neurotransmission at the axon terminal level in the NAS as well as at the cell body level in the VTA. Prominent mutual DA – glutamate interactions exist in the NAS/striatum (Hirata et al., 1984; Cheramy et al., 1986; Kornhuber and Kornhuber, 1986; Kerkerian et al., 1987; Maura et al., 1988; Clow and Jhamandas, 1989; Kalivas et al., 1989; Halpain et al., 1990; Imperato et al., 1990a,b; GarciaMunoz et al., 1991; Lonart and Zigmond, 1991; Ohta et al., 1994), although how exactly glutamate affects dopaminergic transmission (facilitatory versus inhibitory actions, effects on basal versus evoked release of DA, action via NMDA, AMPA/kainate or metabotropic receptors) is not absolutely clear in all aspects. In particular, whether physiological levels of glutamate in the NAS/striatum can increase the release of DA by acting on presynaptic NMDA or AMPA receptors located on dopaminergic terminals (Krebs et al., 1991a,b) is still a matter of debate (see e.g. results and discussion in Romo et al., 1986; Imperato et al., 1990a,b; Keefe et al., 1992; Westerink et al., 1992; Youngren et al., 1993; Ohta et al., 1994). It has been argued that the DA release that is seen only after relatively high doses of glutamate or glutamate agonists represents a non-physiological effect (Svensson et al., 1994b), although quite the opposite effect, i.e. an increase in extracellular levels of DA by low and a decrease of extracellular levels of DA by high doses of glutamate has also been observed (Cheramy et al., 1986; Leviel et al., 1990). The picture is further complicated by the finding that local administration of glutamate receptor antagonists into the NAS also increases extracellular levels of DA (Imperato et al., 1990b; Keefe et al., 1992; Taber and Fibiger, 1995). The available anatomical data does not directly help to resolve this issue since it has been found that the terminals of mPFC efferents in the NAS are often in close apposi-
tion with dopaminergic terminals, but they do not form direct axo-axonic synapses with dopaminergic terminals (Bouyer et al., 1984; Freund et al., 1984; Sesack and Pickel, 1992). Thus, although a direct, ‘point-to-point’ influence of glutamatergic input on the release of DA is not likely based on these anatomical findings, it could nevertheless be possible that extrasynaptic glutamate acts on dopaminergic terminals (‘volume transmission’) (Wightman and Zimmerman, 1990; Zoli et al., 1999). Vice versa, D2 receptors have been shown to be located on the axon terminals of pyramidal cells projecting to the NAS/striatum (Filloux et al., 1988), thus extrasynaptic DA could also potentially affect the release of glutamate at the level of the NAS/striatum. The glutamatergic projection to the NAS does probably not mediate the increase in extracellular DA in the NAS induced by stimulation of the mPFC (e.g. by presynaptically stimulating DA release from dopaminergic terminals in the NAS). In fact, at least for the striatum it has been shown that the large majority of NMDA receptors is located on striatal (spiny) neurons and not on corticostriatal or nigrostriatal terminals (Albin et al., 1992; Wu¨llner et al., 1994a,b). Rather, as mentioned previously, the stimulatory effect of electrical or chemical stimulation of the mPFC on DA release in the NAS appears to mediated by excitatory corticofugal projections to the VTA acting on ionotropic glutamate receptors (Seutin et al., 1990; Suaud-Chagny et al., 1992; Chergui et al., 1993; Wang and French, 1993a,b; White, 1996; Takahata and Moghaddam, 1998) or other structures such as the PPTg which in turn projects back to and excites dopaminergic neurons in the VTA (Scarnati et al., 1986; Di Loreto et al., 1992). Nevertheless, glutamate in the NAS appears to be involved in the regulation of basal DA levels in the NAS/striatum via its action on metabotropic glutamate receptors (Verma and Moghaddam, 1998).
2.3.3.3. Dopaminergic regulation of accumbal glutamatergic afferents. As outlined in the preceding section, glutamate can regulate DA release at the level of the NAS. There is data to suggest that the reverse is also the case, i.e. that dopamine can regulate or at least modulate glutamate release at the level of the NAS. For example, Dalia et al. (1998) have shown that not only systemic but also intra-NAS administration of amphetamine increases extracellular levels of glutamate in the NAS. This effect was blocked by either the D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride. The effect was mimicked by intraNAS co-administration of the D1 receptor agonist SKF38393 and the D2 receptor antagonist quinpirole, but not by either drug alone. However, the results of a number of control experiments led these authors to conclude that the NAS glutamate release caused by DA agonists is neither sufficient nor necessary to produce a
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stimulation of locomotor activity, i.e. the observed increase in glutamatergic transmission appeared to be merely a ‘side effect’ of DA receptor stimulation that was of no direct behavioral relevance. How DA or DA agonists locally increase glutamate levels in the NAS is not clear. A direct, presynaptic stimulatory action on glutamatergic terminals seems unlikely in light of the observation that, at least in the striatum, stimulation of DA receptors attenuates rather than stimulates glutamate release (Rowlands and Roberts, 1980; Godukhin et al., 1984; Maura et al., 1988; Yamamoto and Davy, 1992), although it has been argued that at the level of the VTA D1 receptor agonists can stimulate glutamate release via action on D1 receptors located presynaptically on prefrontal cortical afferents (Kalivas, 1995; Kalivas and Duffy, 1995; Lu et al., 1997b). Alternatively, the effects of DA receptor activation may be mediated via ‘long-loop’ circuits, such that dopaminergic inhibition of striatal or accumbal projection neurons ultimately results in increased activation or decreased inhibition of glutamatergic projections to the striatum or NAS. Strikingly, almost the opposite findings to those of Dalia et al. (1998) described above have been reported by Kalivas and Duffy (1997). Here, intra-NAS infusion of amphetamine reduced levels of extracellular glutamate. This effect was mimicked by the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF82958, and was blocked by SCH23390 and the D2 receptor antagonist sulpiride. The reason for these contrary findings is not clear but may be related to the use of very different drug concentrations in these two studies. While Dalia et al. (1998) infused 10 mM amphetamine, 20 mM SKF38393 and 50 mM quinpirole, the maximum concentration of amphetamine, SKF82958 and quinpirole infused by Kalivas and Duffy (1997) was 100 mM. Thus, Dalia et al. (1998) used concentrations at least 100-fold higher than those used by Kalivas and Duffy (1997). The higher drug doses used by Dalia et al. (1998) could have lost their specificity for the DA transporter and DA receptors. The view that the effects in that study may have been non-specific is also supported by the fact that the results obtained by Kalivas and Duffy (1997) using much lower doses are completely in line with the inhibitory effects of DA on glutamate release in the striatum found in the studies cited above. Taken together, these findings suggest that, as in the striatum, DA in the NAS acts via presynaptic DA receptors (presumably predominantly of the D2 receptor type) to reduce the release of glutamate, which is also consistent with the histological and electrophysiological evidence for the presence of D2 receptors on corticostriatal terminals (Schwarcz et al., 1978; Brown and Arbuthnott, 1983; Filloux et al., 1988; GarciaMunoz et al., 1991).
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2.3.4. The ‘in6erse’ relationship between cortical and subcortical dopamine In the preceding sections, numerous differences between prefrontal cortical and subcortical DA with respect to functional aspects were described. In the following sections of this review, differences between prefrontal cortical and subcortical DA will be discussed on the behavioral level. In many cases, such differences on the behavioral level are paralleled by differences at the neurochemical level. Thus, many of the different functional effects DA produces in mPFC and NAS/ striatum can more or less directly be correlated with specific neurochemical events. With respect to neurochemistry the general picture parallels the one found for motor activity. Increasing dopaminergic transmission within the mPFC leads to a decrease of dopaminergic activity in the NAS, and decreasing mPFC dopaminergic transmission produces increased levels of dopaminergic activity in the NAS. Intra-mPFC injections of amphetamine, cocaine or apomorphine decreased the levels of DA and DA metabolites in the NAS while the injection of a DA antagonist had the opposite effect (Louilot et al., 1989; Jaskiw et al., 1991b; Kolachana et al., 1995). Further evidence for the reciprocal relationship of prefrontal and subcortical DA transmission comes from the finding of Hedou et al. (1999) that after systemic injection of cocaine DA levels in mPFC and NAS showed a significant negative correlation. Unfortunately, the data on the effects of 6-OHDA lesions of the mPFC are less consistent. Such lesions have been shown to enhance K+-stimulated DA release (Thompson and Moss, 1995) and basal extracellular levels of DA and its metabolites in the NAS/striatum (Carter and Pycock, 1978, 1980; Pycock et al., 1980a,b; MartinIverson et al., 1986; Leccese and Lyness, 1987; Haroutunian et al., 1988; Louilot et al., 1989; Kurachi et al., 1995) and also to increase local blood flow in NAS and striatum, an indication of increased metabolic activity (Suzuki et al., 1995). However, a considerable number of studies failed to demonstrate a lesion-induced increase in basal levels of DA or its metabolites after 6-OHDA lesion of the mPFC (Joyce et al., 1983; Dunn et al., 1984; Oades et al., 1986; Swerdlow et al., 1986; Clarke et al., 1988; Bubser and Schmidt, 1990; Schenk et al., 1991; Hemby et al., 1992b; Jones and Robbins, 1992; Rosin et al., 1992; Bubser, 1994; Bubser and Koch, 1994; Sokolowski and Salamone, 1994; Banks and Gratton, 1995; King and Finlay, 1995; McGregor et al., 1996). King and Finlay (1995) also reported that 6-OHDA lesions of the mPFC did not affect the ability of amphetamine to increase extracellular DA in the striatum. On the other hand, Beyer and Steketee (1999) reported that 6-OHDA lesions of the mPFC significantly enhanced the effects of cocaine on extracellular levels of DA in the NAS.
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One possible explanation for the inconsistent findings for 6-OHDA lesions may come from the results of King et al. (1997) who found that 6-OHDA lesions of the mPFC have differential effects on dopaminergic transmission in NAS core and shell. In that study it was found that such lesions did not affect basal DA and stress-induced increase in extracellular DA levels in the core but increased basal DA levels and potentiated the stress-induced DA release in the shell of the NAS. Conversely, the lesions did not alter the ability of systemic amphetamine to increase DA release in the shell but attenuated the amphetamine effect on extracellular DA in the core of the NAS. Because the anatomical, pharmacological, physiological and functional characteristics of the core and shell subareas of the NAS have only been described beginning in the late 1980s (Zaborszky et al., 1985; Voorn et al., 1986, 1989; Zahm and Heimer, 1988, 1993; Zahm, 1991; Berendse et al., 1992; Deutch and Cameron, 1992; Brog et al., 1993), a distinction between core and shell has not been made in most of the earlier studies. Relating to the functional heterogeneity of the mPFC (see section 4), it may be that 6-OHDA lesions of the mPFC in many studies have affected the different subareas to a differential degree, thus differentially affecting DA transmission in NAS core and shell. To the extent that core and shell mediate different behaviors, this would lead to different, ‘inconsistent’ neurochemical effects for the NAS as a whole as well as to ‘inconsistent’ behavioral output (see below). One point to be kept in mind when discussing the subcortical effects of cortical lesions is the extensive collateralization of the mPFC output neurons (Ferino et al., 1987). Thus, manipulations of the mPFC do not only directly affect one given subcortical target area of mPFC efferents but also other subcortical areas, which may then in turn also affect neurochemical or electrophysiological activity in that given subcortical area. Given the complexity of the basal ganglia – thalamocortical circuits in which mPFC efferents are only one of many elements, it may be very difficult to understand and explain the effects of mPFC manipulations on a given subcortical area without consideration of other structures which are also potentially affected by this manipulation. A ‘systems’ approach may therefore be a very important and powerful addition to the focused examination of individual structures in the study of the function of the mesocorticolimbic system. As mentioned above, on a functional level, prefrontal cortical DA appears to exert an inhibitory influence on mesoaccumbens dopaminergic transmission. 6-OHDA lesions of the mPFC were shown to increase the sensitivity of the mesoaccumbal DA projection to footshock stress, i.e. low-intensity footshocks that did not have an effect on NAS DA release in control animals were sufficient to produce a significant release of DA in the
NAS (but not in the dorsal striatum) in lesioned animals (Deutch et al., 1990); likewise, the magnitude of DA release in the NAS induced by a given stressor intensity was larger in animals bearing 6-OHDA lesions of the mPFC as compared to nonlesioned controls (King et al., 1997). This lesion effect seems to be specific for the NAS since similar 6-OHDA lesions of the mPFC did not affect DA release in the neostriatum induced by tail-pressure stress (King and Finlay, 1995). The effect of mPFC DA depletion on subcortical DA responses to stimuli does not seem to be restricted to stress. Rosin et al. (1992) demonstrated that 6-OHDA lesions of the mPFC potentiated the haloperidol-induced increase in tyrosine hydroxylase activity in the NAS, and Mitchell and Gratton (1992) showed that partial DA depletion in the mPFC also enhanced the mesolimbic DA release induced by repeated exposure to naturally reinforcing stimuli such as food or sucrose solution. Thus, it seems as if DA in the mPFC ‘dampens’ the effects of aversive (e.g. stress) as well as rewarding (e.g. food) stimuli on subcortical DA systems, acting as some kind of ‘negative feedback’. A disruption of this inhibitory control in the mPFC might contribute to the exacerbation of symptoms by stress in schizophrenic patients (Weinberger, 1987) or to an increased vulnerability to the addictive effects of drugs (Deminie`re et al., 1988, 1989; Piazza et al., 1991) (see also sections 3.1.4 and 3.4). GABAergic activity in the mPFC and NAS also seems to be differentially regulated by DA. Re´taux et al. (1994) showed that DA denervation by bilateral electrolytic lesions of the VTA resulted in a decrease in GAD67 mRNA levels (glutamic acid decarboxylase, the marker enzyme for GABAergic cells) in the prelimbic area of the mPFC but caused an increase in GAD67 mRNA levels in the shell of the NAS. From this it can be concluded that under physiological conditions DA in the mPFC tonically stimulates GAD67 mRNA expression and thus, presumably, GABAergic activity, while in the NAS shell DA tonically inhibits GAD67 mRNA expression and GABAergic activity. This conclusion is in line with neurochemical and electrophysiological findings that DA in the mPFC generally increases spontaneous GABA release and spontaneous firing of GABAergic neurons (Penit-Soria et al., 1987; Re´taux et al., 1991a,b) and that DA in the NAS generally inhibits the activity of GABAergic spiny neurons (Wilson, 1995). Interestingly, these differences appear to hold only with respect to the basal release of GABA, since electrically- or K+-evoked GABA release is blocked by D2 receptor activation in the mPFC (Re´taux et al., 1991a) as well as in the striatum (Tossman and Ungerstedt, 1986; Bernath and Zigmond, 1989). Taken together, these results suggest that in the mPFC DA exerts a (tonic) stimulatory effect on GABAergic interneurons
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(thereby inhibiting glutamatergic pyramidal cells projecting to the NAS and VTA) whereas in the NAS DA has inhibitory effects on GABAergic spiny neurons. How DA can exert excitatory as well as inhibitory effects via D2 receptors, which are generally coupled to Gi-proteins that inhibit the activity of adenylate cyclase (Seeman and van Tol, 1994), is an unresolved issue. DA release in the NAS and the mPFC has also been shown to be differentially affected by antidepressant drugs of different pharmacological classes and also by a number of non-psychostimulant drugs of abuse. Thus, it has been shown that a clear DA release in the mPFC was induced by doses of antidepressant drugs had no or only small effects on DA release in the NAS (Carboni et al., 1990; Di Chiara et al., 1992; Tanda et al., 1994, 1995, 1996). On the other hand, morphine, nicotine, and ethanol were much more potent in increasing extracellular levels of DA in the NAS as compared to the mPFC (Bassareo et al., 1996). It should be noted, however, that Noel and Gratton (1995) found that intra-VTA injection of the m-receptor agonist DAMGO resulted in DA release of the same magnitude in NAS and mPFC (if anything, the effect in the mPFC tended to be more pronounced and longer-lasting). An observation that may be of relevance for the action of antidepressants and antipsychotics considered in the context of mPFC function is that a2-receptor antagonists markedly increase DA release in the mPFC, an effect that is not seen in the NAS/striatum, and that probably is mediated at the DA nerve terminal level in the mPFC, independently of impulse flow in dopaminergic neurons (Gresch et al., 1995a; Tanda et al., 1996; Gobert et al., 1998; Yamamoto and Novotney, 1998; Hertel et al., 1999). Since ‘atypical’ antipsychotics such as clozapine or risperidone or ‘atypical’ antidepressants such as mianserin or mirtazapine block a2 receptors with relatively high affinity, it has been suggested that this pharmacological property of these drugs contributes to their therapeutic effects (van Dorth, 1983; Nutt, 1994; Davis and Wilde, 1996; Litman et al., 1996; Schotte et al., 1996; Hertel et al., 1997). In any case, the preferential effects of a2-receptor antagonists on mPFC DA release versus NAS DA release are consistent with the relatively high density of a2-receptors in the mPFC (Talley et al., 1996) and the apparent absence of these receptors in the NAS (Schoffelmeer et al., 1998).
3. Behavioral pharmacology of the mesocortical dopamine system
3.1. Reward While an almost overwhelmingly large literature exists concerning the role in reward and reinforcement processes of the VTA and the NAS in general and of
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the mesoaccumbal DA system in particular (for reviews see Koob, 1992; Di Chiara, 1995; Salamone, 1996; Wise, 1996a; Bardo, 1998; Beninger and Miller, 1998; Ikemoto and Panksepp, 1999), the role in reward of the mPFC in general and of prefrontal cortical DA in particular has received considerably less attention and remains rather elusive to date. Nevertheless, there is good evidence that mPFC neurons are involved in reward mechanisms in the brain, although the role of DA in this context is not very well defined (for review, see Tzschentke, 2000).
3.1.1. Conditioned place preference In the conditioned place preference paradigm (CPP), the treatment in question is repeatedly paired with a set of distinct environmental cues, while a neutral control treatment is repeatedly paired with a different set of distinct environmental cues. If the treatment in question is rewarding for the animal, it will, during this repeated pairing, associate these rewarding effects with the distinct environmental cues paired with the treatment. Subsequently, these conditioned, secondary-reinforcing cues will elicit approach behavior, and the animal will thus show a preference for these cues over the neutral cues when given a free choice between them (van der Kooy, 1987; Carr et al., 1989; Tzschentke, 1998). A particular role of the mPFC for cocaine reward effects is seen in place preference studies. While cocaine injected into the mPFC produces CPP (Hemby et al., 1990), amphetamine (Carr and White, 1986; Schildein et al., 1998) as well as morphine and the m-opioid receptor agonist DAMGO (Bals-Kubik et al., 1993; Olmstead and Franklin, 1997) injected into the mPFC fail to do so. Interestingly, the opposite is true for injections of the drugs into the NAS (van der Kooy et al., 1982; White et al., 1985; Hemby et al., 1992a; Olmstead and Franklin, 1997) (see Tzschentke, 1998, for a recent review of available CPP data). On the other hand, it has been shown that 6-OHDA lesions of the mPFC, in contrast to the effects of these lesions on intra-mPFC self-administration of cocaine (see below), did not affect the place preference conditioning induced by systemically administered cocaine (Hemby et al., 1992b) and morphine (Shippenberg et al., 1993), showing that reward can be produced by systemically administered drugs independently of prefrontal cortical DA. However, although the rewarding effects of drugs may be independent of prefrontal cortical DA, they may nevertheless depend on overall mPFC function. This is suggested by the finding that quinolinic acid-induced lesions of the mPFC, and even of specific subareas of the mPFC, can block cocaine-, morphine- and CGP37849-induced CPP (Tzschentke and Schmidt 1998a,b, 1999). In these experiments, by including an additional test with drugged animals, it was possible to exclude the possibility that the lesions
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made the acquired CPP state-dependent. In other studies it was shown that mPFC lesions did not affect stimulus-reward learning in classical and operant conditioning paradigms (Isaac et al., 1989; Burns et al., 1993; Bussey et al., 1996) leaving a reduction/blockade of the rewarding effects of the drugs by the mPFC lesions as the most likely interpretation of the CPP results. Another issue to be considered when discussing the effects of drugs or lesions on CPP, especially in cases where the development of CPP was blocked by lesions of or drug injections into the mPFC, is that an observed blockade of CPP might not be due to the disruption of the primary rewarding effects of the drugs or to the disruption of conditioning, but might rather be due to a disruption of the discriminative stimulus properties of the drugs used to establish CPP. Unfortunately, although an extremely large drug discrimination literature exists, only very few studies have addressed the question of which central sites mediate the discriminative stimulus properties of drugs, and apparently nothing is known about the role of the mPFC. Nevertheless, the existing data appears to suggest that structures other than the mPFC may be responsible for the mediation of the stimulus properties of morphine (Jaeger and van der Kooy, 1993; Shoaib and Spanagel, 1994), amphetamine (Nielsen and Scheel-Kru¨ger, 1986; Druhan et al., 1993) and cocaine (Callahan et al., 1997). No relevant data seem to exist for NMDA receptor antagonists. In any case, although no direct evidence exists, it would appear unlikely that the mPFC is involved in the mediation of the discriminative stimulus properties of drugs to the extent that lesioning or pharmacological manipulation of this area would disrupt CPP.
3.1.2. Self-administration In self-administration experiments an animal is implanted with an intravenous catheter or an injection canula directly into a discrete brain region. If a peripheral or central drug injection is experienced as rewarding by the animal, it will learn to perform an operant response (usually lever-pressing or nose-poking) to obtain drug injections (Koob and Goeders, 1989; Richardson and Roberts, 1996). One line of evidence suggesting a role of the mPFC in reward derives from electrophysiological and electrochemical recordings during drug self-administration behavior. When activity of mPFC cells was recorded during drug self-administration, it was found that the firing of mPFC cells can be very closely time-locked to the i.v. injections of cocaine and heroin (Chang et al. 1997a,b, 1998). Likewise, when DA release in the mPFC was monitored during response-contingent delivery of liquid reward using voltammetry, it was found that the DA signal or DA cell activity showed changes time-locked to the delivery of the reward (Richardson
and Gratton, 1998). Qualitatively quite similar timelocked responses have also been found in prefrontal cortical cells of the monkey in an equivalent experimental task (Ono et al., 1984; Watanabe, 1996). Interestingly, in the study of Richardson and Gratton (1998) DA responses were minor when animals consumed a standard reward under a continuous reinforcement schedule but were particularly evident under delayed reinforcement and unexpectedly altered reinforcement conditions. With delayed reinforcement, lever presses were followed by DA signal increases during the delay period and subsequent decreases in the DA signal after the reward had been delivered. Withholding expected reward or delivering a smaller or greater than expected reward also resulted in DA signal increases. Based on these results, the authors suggested that ’’the DA input to PFC is activated when rewards are presented under conditions that deviate from those that the animals had come to expect, particularly so when the temporal structure of learned associations is altered’’ (Richardson and Gratton, 1998, p. 9130). These results are in striking accordance with the findings of Schultz and collegues for the firing behavior of VTA DA neurons under different reinforcement conditions. Here, responses were found to be negligible when familiar rewards were earned and consumed under standard conditions but were found to be most pronounced when a new, unexpected reward or a change in the reinforcement contingencies (withholding an expected reward, delaying reward delivery or delivering the reward earlier than expected, diminishing or increasing the reward magnitude) was encountered (Ljungberg et al., 1992; Schultz, 1986; Schultz et al., 1993, 1997; Guigon et al., 1995). It is tempting to assume that changes in dopaminergic transmission in the mPFC as shown by Richardson and Gratton (1998) are a direct consequence of the alterations in DA cell firing as demonstrated by Schultz and collegues, and that, in turn, the alterations in mPFC pyramidal cell firing as shown by Ono et al. (1984) and Watanabe (1996) are a consequence of alterations of dopaminergic transmission in the mPFC. Unfortunately, although quite extensive mircodialysis data exists about the consequences of drug self-administration on NAS DA levels (e.g. Gratton and Wise, 1994; Wise et al., 1995a,b), apparently no comparable data are available for the mPFC.
3.1.2.1. Intracranial self-administration. Evidence that an elevation of extracellular DA within the mPFC has direct rewarding effects is limited. Thus, it has been shown that cocaine and DA itself is self-administered into the mPFC (Goeders and Smith, 1983, 1986, 1993; Goeders et al., 1986) but not into the NAS (Goeders and Smith, 1983), whereas, surprisingly, the reverse is true for amphetamine, i.e. amphetamine is self-adminis-
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tered into the NAS (Hoebel et al., 1983) but not into the mPFC (Goeders et al., 1986). Co-infusion of the D2 receptor antagonist sulpiride attenuated and 6-OHDA lesions of the mPFC abolished intra-mPFC self-administration of cocaine while the D1 receptor antagonist SCH23390, the beta-noradrenergic receptor antagonist propranolol and the muscarine receptor antagonist atropine were without effect (Goeders and Smith, 1983, 1986; Goeders et al., 1986), pointing to a pivotal role of DA in the mPFC for the rewarding effects of locally injected cocaine that is mediated primarily by D2 receptors. Nevertheless, mechanisms including other transmitters such as noradrenaline or serotonin cannot be completely excluded based on these findings, particularly since cocaine also blocks the reuptake of noradrenaline and serotonin (Yu and Smith, 1977; Taylor and Ho, 1978; Hadfield et al., 1980) and since complex interactions between the various transmitters within the mPFC have been described (see sections above). Another point that has to be considered, especially in the light of the observation that amphetamine, which is self-administered into the NAS (Hoebel et al., 1983), does not sustain self-administration into the mPFC (Goeders et al., 1986) is that the rewarding actions of cocaine may be due to its local anesthetic effects. If inhibition/inactivation of mPFC efferents was an important element in the mediation of reward, then cocaine, due to its local anesthetic properties, would be expected to produce reward independently of its effects on extracellular DA. However, the results of Goeders et al. (1986) suggest that the local anesthetic properties of cocaine are not responsible for its rewarding effects in the mPFC since the cocaine effect was not mimicked by local infusion of lidocaine. Nevertheless, this does not necessarily exclude the possibility that the lack of selfadministration of cocaine into the NAS is due to its local anesthetic properties in addition to and in combination with its other pharmacological properties. We are unaware of any reports addressing this question directly, e.g. by combining amphetamine (which is selfadministered into the NAS) with a local anesthetic such as lidocaine to mimic that particular pharmacological effect of cocaine. Most interestingly, Goeders and Smith, after reviewing their own and other data, conclude that ‘‘these data suggest that cocaine microinjections into the medial prefrontal cortex produce neurochemical and behavioral effects similar to those observed after destruction of the dopaminergic innervations of the prefrontal cortex.’’ (Goeders and Smith, 1993, p. 598). However, how this rather paradoxical effect is mediated remains unknown. One point that might be of relevance in the present context is the fact that intracranial self-administration measures not simply reward per se. Animals perform an operant task in order to earn a drug injection, i.e. they have to be motivated to perform this task. Initially, they have
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learn the association between the operant task and the rewarding effects of the response-contingent drug-infusion, and subsequently they have to recall this association to guide their behavior. Animals also have to make selective responses towards the drug-associated lever and have to suppress other behaviors. Thus, incentive motivation, reward, learning, memory, retrieval of this memory, behavioral inhibition, and response selection are all involved in the acquisition and maintenance of the self-administration behavior, and, as outlined in section 3.4, it is well known that the mPFC plays an important role in working memory and response selection based on temporal contingencies. It might therefore be that the reason why cocaine is self-administered into the mPFC but amphetamine is not lies not in the fact that cocaine produces reward when injected locally and amphetamine does not, but that cocaine, due to some as yet unknown properties, does not interfere with the ‘cognitive functions’ of the mPFC necessary to establish and maintain self-administration behavior, while amphetamine disrupts learning, memory, response selection or some other process important for self-administration. Comparative studies examining the effects of intra-mPFC injections of cocaine and amphetamine in cognitive tasks would be necessary to test this possibility. This interpretation, however, is supported by the findings of Richardson and Gratton (1998) discussed above and also by other evidence suggesting that prefrontal cortical DA is not a reward signal per se, produced by the consumption of a reward, but rather is associated with novelty, ‘excitement’ (i.e. mild stress), expectancy, and operant and classically conditioned responses (D’Angio and Scatton, 1989; Hernandez and Hoebel, 1990; Cenci et al. 1992; Feenstra and Botterblom, 1996; Bassareo and Di Chiara, 1997). It should be noted here, however, that there is some controversy about whether conditioned stimuli elicit DA release within the mPFC. Whereas there is good evidence that food- or drug-associated stimuli can increase DA transmission in the NAS (Phillips et al., 1993; Gratton and Wise, 1994; Richardson and Gratton, 1996), data concerning DA transmission in the mPFC in response to conditioned stimuli is inconsistent. While Richardson and Gratton (1998), Carey and Damianopoulos (1994) found no indication of conditioned DA responses in the mPFC, Bassareo and Di Chiara (1997) showed that stimuli associated with food increased extracellular levels of DA in the mPFC. In studies involving aversive conditioning a conditioned increase in mPFC DA release (Herman et al., 1982; Wedzony et al., 1996; Yoshioka et al., 1996) as well as not effect (Wilkinson et al., 1998) was observed. Since there are several important procedural differences between these studies (voltammetry versus microdialysis, resulting in different sampling area and sampling resolution; classical versus operant condition-
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ing, which may involve different neuronal mechanisms; use of rewarding versus aversive unconditioned stimuli; different handling and habituation procedures, see Feenstra et al., 1999) it is difficult, based solely on these studies, to draw any firm conclusions about the role of the mesocortical DA projection in conditioning processes. Interestingly, the non-competitive NMDA receptor antagonists PCP and MK-801 and the competitive NMDA receptor antagonist CPP are not only self-administered into the NAS shell but also into the mPFC (Carlezon and Wise, 1996a). While in this study it was shown that the self-administration of NMDA-receptor antagonists into the NAS shell was independent of dopaminergic mechanisms (as demonstrated by the failure of sulpiride co-infusion to affect self-administration behavior), unfortunately the same test was not done for the mPFC. Thus, it is not known whether the rewarding effects of NMDA-receptor antagonists when injected into the mPFC are mediated by a local increase in extracellular DA induced by these drugs. However, this possibility seems unlikely for two reasons. Firstly, although PCP at higher doses also has DA uptakeblocking effects, the relatively low doses of PCP used in the above-mentioned study should not be expected to have such an effect. Furthermore, MK-801 and CPP are not known to possess DA uptake-blocking effects. Thus, it seems unlikely that these drugs increase extracellular DA via a local, pharmacologically specific effect. Secondly, given the reciprocal relationship between dopaminergic activity in the mPFC and in the NAS (see section 2.3.4), a mediation via a dopaminergic mechanism would be difficult to explain. Since DA in the mPFC generally inhibits glutamatergic efferents, an increase in mPFC DA would result in reduced excitatory drive to the VTA, and consequently, to reduced DA release in the NAS, which is incompatible with the proposed role of NAS DA in reward mechanisms. Findings that pose considerable interpretational problems have been reported by David et al. (1998). These authors showed that AMPA and NMDA receptor antagonists are self-administered into the VTA, implicating that these injections produced rewarding effects. When self-administration behavior was established peripheral administration of the D2 receptor antagonist sulpiride produced extinction-like responding, indicating that the rewarding effects of the self-administered glutamate antagonists were dependent on dopaminergic neurotransmission, presumably manifest as an increase in NAS DA release. This is incompatible with the notion that the rewarding effects of mPFC stimulation are ultimately mediated by increased glutamatergic activation of VTA DA neurons. It is also incompatible with the observation that at the level of the VTA glutamate agonists rather than antagonists produce burst firing in DA neurons (see section 2.3.2.1).
The finding of David et al. (1998) would implicate that glutamatergic input to the VTA predominantly terminates on inhibitory GABAergic interneurons and that this input exerts, via these interneurons, a tonic inhibitory influence on dopaminergic neurons, such that injection of a glutamate antagonist would reduce excitatory input onto GABAergic neurons and would thus relieve the dopaminergic neurons from tonic GABAergic inhibition. Although this is consistent with the fact that the GABA-A receptor antagonist bicuculline is self-administered into the VTA (David et al., 1997; Ikemoto et al., 1997), it is difficult to reconcile with the numerous findings mentioned in previous sections that glutamatergic input to the VTA has potent excitatory effects on dopaminergic activity (with respect to firing of DA neurons, reward, locomotion). It is also inconsistent with the finding of Mathe´ et al. (1998) that locomotor activity and DA release in the NAS produced by systemic administration of MK-801 was antagonized by intra-VTA infusion of the AMPA/kainate receptor antagonist CNQX. In the same study VTA CNQX infusion itself did not have any behavioral effects and also had no effects on DA levels in the NAS. This apparent ineffectiveness of CNQX is difficult to reconcile with its presumed rewarding effects after intra-VTA injection. A hypothetical scenario that could resolve these apparent inconsistencies would involve presynaptic inhibitory autoreceptors on glutamatergic terminals in the VTA. If this were the case, glutamate antagonists, by blocking these autoreceptors, would increase extracellular glutamate in the VTA which would increase activity of DA neurons and DA release in the NAS, and would therefore have the same effects as glutamate agonists acting directly on postsynaptic glutamate receptors on the cell bodies of DA neurons. To our knowledge experimental evidence for or against this scenario is not available. At least in the striatum and hippocampus glutamate release appears to be under tonic inhibition via NMDAand AMPA receptors, although in this case, too, an indirect mechanism involving GABAergic neurons cannot be excluded (Liu and Moghaddam, 1995). Clearly, much more work is needed to resolve these issues.
3.1.2.2. Lesion effects on intra6enous self-administration. Weissenborn et al. (1997) showed that quinolinic acid lesions of the mPFC facilitated acquisition of cocaine IV self-administration under a fixed ratio schedule. Also, under a second-order schedule of reinforcement lesioned rats showed higher rates and disrupted pattern of responding compared to control rats. This responding was not affected by omission of the conditioned stimulus in the lesioned animals. On the other hand, acquisition of responding for a non-drug reinforcer, sucrose, was not affected by the lesion. The authors interpreted their findings not in terms of an enhancement of cocaine reward by the lesion but in terms of
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deficits in behavioral inhibition induced by the mPFC lesions (see also Ravard et al., 1990; Burns et al., 1993, 1996; Granon et al., 1994; Broersen et al., 1995, 1999; Muir et al., 1996; Jinks and McGregor, 1997; see also section 3.4). According to this interpretation, ‘‘rats with medial prefrontal cortex lesions are more likely than controls to explore the self-administration chamber during the initial stages of testing, approaching the lever that delivers cocaine more frequently, and therefore self-administering more drug during acquisition.’’ (Weissenborn et al., 1997, p. 252). It has also been shown that rather large ibotenic acid lesions of the mPFC did not affect voluntary ethanol intake in rats (Hansen et al., 1995) and that temporary inactivation by injection of lidocaine into the prelimbic subarea of the mPFC did not affect responding in a fixed-interval lever pressing task for food reward (Evans and Cory-Slechta, 2000). On the other hand, relatively large electrolytic lesions of the frontal cortex decreased the reinforcing effects of self-administered morphine (Trafton and Marques, 1971; Glick and Cox, 1978). As shown by Goeders et al. (1986) co-infusion of the D1 antagonist SCH23390 was without effect on intracranial self-administration of cocaine. On the other hand, intra-mPFC injection of SCH23390 was shown to reduce the rewarding effects of i.v. self-administered cocaine (McGregor and Roberts, 1995). Also, 6-OHDA lesions of the mPFC actually enhanced the rewarding effects of intravenously self-administered cocaine in two studies (Schenk et al. 1991; McGregor et al. 1996) while having no effect in another study (Martin-Iverson et al. 1986) and also having no effect on either acquisition or maintenance of i.v. amphetamine self-administration (Leccese and Lyness 1987). The apparent discrepancy between the findings of Goeders and Smith versus McGregor et al. and Schenk et al. regarding the effects of mPFC 6-OHDA lesions on cocaine self-administration may be due to a differential degree of DA depletion at the site of cocaine action within the mPFC, as discussed by Bardo (1998). According to this interpretation, in the Goeders and Smith study, by injecting 6-OHDA through the self-administration canula, a very focussed but complete DA depletion at the site of cocaine action may have been achieved, yielding extinction-like responding although overall DA depletion of the whole mPFC was low. On the other hand, in the other two studies, although 6-OHDA lesions resulted in a higher overall DA depletion in the mPFC, a population of DA axon terminals is likely to have survived, at least at some distance from the site of injection of 6-OHDA. Since after systemic administration cocaine will reach much larger sections of the mPFC than after local injection, cocaine could have acted on these remaining terminals which, together with the presumed denervation supersensitivity of postsynaptic DA recep-
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tors, resulted in an even enhanced rewarding effect of cocaine in the two latter studies. Another point to be considered are the procedural differences between these self-administration studies. Schenk et al. (1991) and McGregor et al. (1996) reported that 6-OHDA lesions of the mPFC enhanced the rewarding effects of low ( 0.1–0.25 mg/kg/inf.), but not of high ( 0.4–1.5 mg/kg/inf.) unit doses of IV cocaine, indicating that drug dose may be an important factor determining the outcome of an experiment. Because of the local route of drug administration it is difficult determine how the doses of cocaine used in the Goeders and Smith study relate to ‘high’ and ‘low’ IV unit doses, but the unit dose used by Martin-Iverson et al. (1986) would fall into the ‘high’ dose category in the studies of Schenk et al. and McGregor et al. which might well explain the lack of lesion effect observed by Martin-Iverson et al. (1986). In addition, further procedural differences between these studies exist. Schenk et al. (1991) tested the lesion effects on the acquisition and maintenance of self-administration behavior under a fixed-ratio schedule of reinforcement, McGregor et al. (1996) tested the lesion effects on maintenance of selfadministration under a progressive-ratio schedule, while Goeders and Smith (1986) and Martin-Iverson et al. (1986) used yet another combination of parameters, in that they tested the effects of the lesions on maintenance under a fixed-ratio condition. These factors make the comparison of these studies quite difficult, and it may be of relevance here that the outcome of a self-administration experiment can actually depend on whether fixed ration or progressive ratio schedules are used. Thus, McGregor and Roberts (1995) found that under an FR1 schedule the D1 receptor antagonist SCH23390 produced an increase in the rate of cocaine intake following injection into either mPFC or striatum; in contrast, under a PR schedule similar injections into the striatum had no effect on the breaking point while large decreases in breaking point were produced by intra-mPFC injections of the drug. This indicates that the two schedules measure different aspects of the reinforcing actions of cocaine. The reason for this is unclear, but it shows that one has to be cautious when comparing results from self-administration studies that have used different schedules of reinforcement (see also McGregor and Roberts, 1993, 1995, for further discussion of this point).
3.1.3. Self-stimulation Perhaps the most obvious evidence that the mPFC participates in brain reward mechanisms is the wellknown observation that the mPFC supports electrical intracranial self-stimulation (ICSS). In intracranial selfstimulation experiments a stimulating electrode is implanted into a discrete brain region. If the electrical stimulation of this region is experienced as rewarding
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by the animal, it will learn to perform an operant response (usually lever-pressing or nose-poking) to obtain this stimulation (Stellar and Rice 1989; Phillips and Fibiger 1989). Although the rates of responding obtained for ICSS in the mPFC are generally lower than the rates obtained for VTA or MFB self-stimulation, very robust and reliable self-stimulation behavior can be obtained with electrodes in the mPFC. Although this phenomenon has long been known and has received a lot of interest (Routtenberg and Sloan, 1972; Mora, 1978; Phillips and Fibiger, 1978; Ferrer et al., 1983; Mora and Ferrer, 1986; Mora and Cobo, 1990), the underlying neurophysiological and neuropharmacological mechanisms are still somewhat elusive. While VTA or MFB ICSS is not affected by 6-OHDA lesions or by injection of neuroleptics into the mPFC (Mogenson et al., 1979; Simon et al., 1979b), it seems well established that the rewarding effects of VTA and MFB self-stimulation involve subcortical dopaminergic mechanisms (e.g. Fouriezos et al., 1978; Phillips and Fibiger, 1978; Mogenson et al., 1979; Fibiger et al., 1987; Gratton et al., 1988; Phillips et al., 1989; Nakahara et al., 1989a,b, 1992; Manley et al., 1992; Fiorino et al., 1993; but see Gallistel, 1986; Miliaressis et al., 1991; Bauco et al., 1994; Hunt and McGregor, 1998 for findings that question the role of DA as the ultimate mediator of MFB or VTA ICSS). On the other hand, there is considerable disagreement in the literature about the extent to which mPFC ICSS is dependent upon dopaminergic mechanisms. Early studies have demonstrated a rather striking overlap between those regions of the prefrontal cortex that sustain ICSS (Routtenberg and Sloan, 1972) and those regions of the prefrontal cortex that receive a dense dopaminergic innervation (Thierry et al., 1976b). Furthermore, mPFC ICSS has been shown to clearly increase DA release in the same region (Mora, 1978). From these observations it seemed intuitive to assume that the ability of prefrontal cortical regions to sustain ICSS is somehow linked to its dopaminergic innervation. However, behavioral and pharmacological evidence for this assumption is inconsistent, with respect to the role of prefrontal cortical DA as well as with respect to the role of DA in general. Some studies have shown that the rewarding effects of the stimulation (in terms of rates of responding) can be decreased by administration of DA antagonists and increased by administration of DA agonists (Phillips and Fibiger, 1978; Robertson and Mogenson, 1978; Ferrer et al., 1983; Hand and Franklin, 1983; Moody and Frank, 1990; Mora and Cobo, 1990; McGregor et al., 1992; Sabater et al., 1993), but other studies showed a relative independence of mPFC ICSS of dopaminergic mechanisms in comparison to MFB or VTA ICSS (Carey et al., 1975; Mora et al., 1977; Phillips and Fibiger, 1978; Mogenson et al., 1979; Simon et al., 1979b; Robertson et al., 1981; Phillips et al., 1987, 1992; Nakahara et al.,
1989b; Corbett, 1990; Singh et al., 1997). Chemical (Murase et al., 1993a; Karreman and Moghaddam, 1996) and electrical (Taber and Fibiger, 1993, 1995; Taber et al., 1995; You et al., 1998) stimulation as well as electrical self-stimulation of the mPFC (You et al., 1998, Tzschentke et al. unpublished observations) increases extracellular levels of DA in the NAS. If this stimulation-induced increase in NAS DA is blocked by intra-VTA infusion of the glutamate receptor antagonist kynurenic acid (presumably by blocking the excitatory glutamatergic input from prefrontal cortical afferents onto DA cell bodies), self-stimulation behavior is not sustained, indicating that the stimulation has lost its rewarding effects (You et al., 1998, Tzschentke et al., unpublished observations). These findings would argue that DA does have a role in the mediation of the rewarding effects of mPFC ICSS. When considering the effects of DA antagonists on mPFC ICSS it has to be kept in mind that many of the early studies used rate-dependent measures of responding, thus making the interpretation of decreases of responding by dopaminergic antagonists difficult. To our knowledge, it has not been tested to date whether mPFC ICSS can be established in animals bearing 6-OHDA lesions of the mPFC, i.e. whether the rewarding effects of mPFC ICSS involve stimulation-induced DA release within the mPFC. A similar experiment involving the sulcal prefrontal cortex, however, has been performed by Clavier and Gerfen (1981) who showed 6-OHDA lesions of this region only transiently and mildly disrupted ICSS at the same site. On the other hand, microinjections of kainic or ibotenic acid at the tip of the electrode supporting mPFC ICSS almost completely abolished self-stimulation behavior (Ferrer et al., 1985; Nassif et al., 1985). Thus, taken together, the available evidence appears to suggest that the primary effect of electrical mPFC stimulation is the activation of (direct or indirect) glutamatergic input to the VTA, which in turn increases subcortical DA release (Fiorino et al., 1993; Taber et al., 1995; Tzschentke et al., 1997; Rossetti et al., 1998; You et al., 1998). An explanation for the partly inconsistent findings concerning the role of DA in mPFC ICSS might be found in the anatomical organization of the mPFCVTA-NAS circuit. As mentioned previously, the majority of glutamatergic afferents to the VTA have been shown to synapse on non-dopaminergic cells (i.e. presumably GABAergic neurons) in the VTA (Sesack and Pickel, 1992). Given that a GABAergic projection from the VTA to the NAS/striatum also exists (van Bockstaele and Pickel, 1995) which terminates predominately on cholinergic interneurons (Pickel and Chan, 1990), it might be that the glutamatergic prefrontal cortical input to the VTA terminates predominantly not on GABAergic interneurons that would in turn inhibit dopaminergic neurons but rather on those GABAergic
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cells that project to subcortical targets. Thus, glutamatergic input to the VTA would lead to inhibition of the cholinergic interneurons in NAS/striatum, thereby decreasing excitatory cholinergic input to medium spiny neurons. This sequence of events would ultimately have the same (inhibitory) effects on NAS output neurons as DA released from the ‘direct’ dopaminergic input via a mPFC-VTA-NAS pathway. If this ‘indirect’ pathway outlined above was more important for the rewarding effects of mPFC ICSS than the ‘direct’ pathway, this would explain why the rewarding effects of mPFC ICSS appear to be mediated via glutamatergic transmission in the VTA yet seem to be relatively independent of dopaminergic mechanisms. This would mean, however, that the observed blockade of both DA release in the NAS and self-stimulation behavior by infusion of the glutamate antagonist kynurenic acid into the VTA (Tzschentke et al., 1997; You et al., 1998) are not causally related. According to this view, kynurenic acid in the VTA would block the rewarding effects of mPFC ICSS not because it blocks activation of mesoaccumbal DA neurons but rather because it blocks activation of mesoaccumbal GABA projections. The dichotomy between prefrontal cortical and subcortical DA with respect to reward is also exemplified by the findings of Duvauchelle et al. (1998). In this study it was shown that injections of the D1 antagonist SCH 23390 into the NAS increased reward thresholds (i.e. reduced the rewarding effects) of electrical VTA stimulation while injection of the same dose of SCH 23390 into the mPFC actually lowered reward thresholds (i.e. increased the rewarding effects) of the stimulation. Consistent with the latter finding, injection of the D2 antagonist flupenthixol into the mPFC also enhanced the rewarding effects of electrical VTA stimulation as measured with the place preference conditioning paradigm (Duvauchelle et al., 1992). In line with these findings is also the fact that DA agonists infused into the NAS enhance while DA agonists infused into the mPFC attenuate the rewarding effects of medial forebrain bundle ICSS (Olds, 1990). All these findings suggest that, as in the case of locomotion (see section 3.2), DA in the mPFC acts to oppose or to dampen the effects of DA in the NAS. The anatomical substrates mediating the rewarding effects of mPFC stimulation are not entirely clear. In particular, there is some debate about the extent to which ICSS produced at different sites (e.g. mPFC, VTA, MFB) are mediated by common anatomical circuits. There is considerable evidence that the primary substrate of ICSS in mPFC and MFB (i.e. the fibers/ cells that are directly activated by the stimulation) have different electrophysiological properties (Gallistel et al., 1981; Schenk and Shizgal, 1982, 1985; Schenk et al., 1985), and the different behavioral response characteristics for stimulation of the two sites (Douglin and
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Glassman, 1979; Corbett et al., 1982a, 1985; Corbett and Stellar, 1983; McGregor, 1992) also suggests that different substrates are involved. Furthermore, mPFC ICSS is not affected by lesions of the MFB, the NAS and the MD thalamus (Corbett et al., 1982b), and vice versa, even large ablations of the frontal cortex had no or only marginal effects on MFB ICSS (Stellar et al., 1982; Colle and Wise, 1987). On the other hand, the rewarding effects of ICSS in mPFC and MFB summate, at least in part (Schenk and Shizgal, 1982; Conover and Shizgal, 1992; see also Trzcinska and Bielajew, 1998), and immunohistochemical studies have detected some degree of overlap of regions expressing Fos after mPFC and MFB (self-)stimulation (see Arvanitogiannis et al., 1996, 1997a,b, 2000; Flores et al., 1997; Hunt and McGregor, 1998). However, rather surprisingly in the light of the proposed role for DA in mPFC and MFB ICSS (see above), only little Fos-expression was found in dopaminergic VTA cells after self-stimulation of both structures (Hunt and McGregor, 1998; Arvanitogiannis et al., 2000). A striking feature of mPFC ICSS, as compared to MFB or VTA ICSS, is the very slow rate of acquisition. While rats implanted with electrodes into the MFB or VTA commonly acquire lever-press behavior within a few training sessions (sometimes even within one training session of a few minutes), it may take a few weeks to establish reliable lever-pressing in rats with electrodes implanted into the mPFC, and often a considerable amount of shaping is required to establish the behavior at all (Douglin and Glassman, 1979; Corbett et al., 1985; Robertson, 1989; Mora and Cobo, 1990; McGregor, 1992). The reason for these particular properties of mPFC ICSS may relate to one or more of the following possibilities: (1) As outlined in section 3.4, the mPFC is likely to be involved in processes of behavioral inhibition. Notably, it has been observed that stimulation of the mPFC during initial training sessions inhibits ongoing behavior, in other words, lever-pressing suppresses the further expression of this very behavior (Corbett et al., 1985; McGregor, 1992). It has also been observed that acquisition speed was negatively correlated to the degree of motor inhibition caused by initial stimulation (Spence et al., 1985; McGregor, 1992). Furthermore, non-contingent stimulation of the mPFC can inhibit bar pressing for food, and open field and running wheel activity (Wilcott, 1981; Corbett and Stellar, 1983; Spence et al., 1985). Thus, it is conceivable that acquisition of mPFC ICSS proceeds in parallel to a tolerance towards the inhibitory effects of the stimulation. This is consistent with the observation that prior, pre-training non-contingent stimulation of the mPFC facilitates subsequent acquisition of lever-press behavior (Corbett et al., 1982a). However, this latter observation could also be interpreted in terms of two further possible explanations for the slow acquisition of
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mPFC ICSS. (2) There is also evidence that the mPFC is involved in emotional processes, and McGregor (1992) has found that the rate of acquisition of mPFC ICSS is negatively correlated to the aversive effects of initial stimulation (in terms of defaecation). Furthermore, it has been found that in stimulation-naive rats non-contingent stimulation of the mPFC produced a conditioned place aversion while in stimulation-experienced rats this aversion was no longer present (unpublished results, cited in McGregor, 1992). Thus, it may be that acquisition of mPFC ICSS is determined by the degree of tolerance to the aversive effects of the stimulation. (3) The observation that non-contingent prestimulation facilitates subsequent acquisition of self-stimulation can also be interpreted in yet another way. It may be that initially the stimulation only produces very weak, if any, rewarding effects, and that only with repeated and prolonged stimulation the rewarding effects of the stimulation sensitize to a degree that self-stimulation behavior is initiated and sustained. However, Corbett et al. (1985) found gradual increases in rate of lever-pressing but no evidence for a concurrent increase in rewarding effects of the stimulation (in terms of frequency thresholds) during prolonged training. (4) Finally, Fuster (1980) has shown that stimulation of the prefrontal cortex can disrupt the learning of delayed alternation and delayed response tasks. Thus, it is conceivable that the eventual acquisition of an instrumental response requires a progressive tolerance to these learning-disrupting effects during pre-training stimulation or training. In fact, Corbett et al. (1985) showed that if an instrumentally less complex response such as nose poking is required for self-stimulation, the acquisition of the response is facilitated. Of course, these above-mentioned possibilities are by no means mutually exclusive. It may be that the behavioral inhibition caused by the stimulation is experienced as aversive, or, vice versa, that the aversive stimulation effects inhibit ongoing activity. Also, it may be very difficult, experimentally and semantically, to see whether the increase in lever-pressing is due to a tolerance towards the aversive effects, thereby progressively ‘unmasking’ the rewarding effects of the stimulation, or whether the sensitization of the rewarding effects of the stimulation with a concurrent progressive ‘masking’ of the aversive effects is the primary cause for the increase in leverpressing. The picture that emerges from the available (but rather limited) literature suggests that all 4 of the above-mentioned mechanisms may contribute to the slow emergence of lever-pressing for mPFC ICSS, although several findings from the elegant study of Corbett et al. (1985) who have examined most of the alternatives outlined above suggest that the reward sensitization explanation may not be valid. However, there are still questions in this field that remain unanswered, but unfortunately, to our knowledge, there
have been no more publications addressing these issues for almost a decade. Finally, ICSS of the mPFC also provides further evidence for the notion that the mPFC is differentially involved in the mediation of the rewarding effects of drugs and that the integrity of this structure may be more important for the effects of some drugs (in particular cocaine) than for others (in particular amphetamine). Thus, while the rewarding effects of MFB self-stimulation are enhanced by various drugs of abuse (see Wise, 1996b, for review), the reward value of mPFC self-stimulation is only enhanced by cocaine and MK-801 but not by amphetamine or morphine (Spence et al., 1985; Corbett, 1989, 1991, 1992; Moody and Frank, 1990; McGregor et al., 1992).
3.1.4. Addiction and cra6ing There is evidence that the mPFC is involved not only in the mediation of the primary rewarding effects of drugs but also in neural mechanisms underlying addiction and craving. Recently, it has been demonstrated that the mPFC is actively involved in aspects of addictive behavior. Functional imaging studies in humans have shown that the mPFC is strongly activated by cocaine itself (Breiter et al., 1996), during cocaine withdrawal (Volkow et al., 1991, 1996) and, most interestingly, during cue-induced craving (Childress et al., 1996, 1999; Grant et al., 1996; Maas et al., 1998). Also, the prelimbic mPFC was among those brain sites that showed the strongest Fos expression induced by beer craving in the rat (Topple et al., 1998). Interesting evidence for an involvement of the (anterior cingulate area of the) mPFC was also reported by Neisewander et al. (2000). These authors found that exposure to a cocaine self-administration environment enhanced Fos expression in the mPFC, basolateral amygdala, NAS and some other brain areas, suggesting that this pattern of Fos expression is related to the conditioned (reinforcing) effects of cocaine. Priming injections of cocaine enhanced Fos expression in the VTA, striatum, lateral amygdala and some other brain areas. There was no difference between a group that had never received cocaine before, a group that had been self-administering cocaine and underwent extinction subsequently, and a group that had been self-administering cocaine and did not undergo extinction subsequently. This suggests that the observed pattern of Fos expression reflects the primary, unconditioned effects of cocaine. Interestingly, the anterior cingulate mPFC was the only area that showed Fos expression in response to a priming injection of cocaine only in the cocaine-experienced groups but not in the group that had never experienced cocaine before. This suggests that the enhanced Fos expression in this area reflects an experience-dependent (motivational) effect of the priming injections. Thus, in this study the anterior cingulate mPFC appeared to be the
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only area that responded to conditioned cocaine effects and showed an experience-dependent response to unconditioned cocaine effects. Dopaminergic activity is reduced in the mPFC (while it is increased in the NAS) of rats predisposed to rapid acquisition of amphetamine IV self-administration (Piazza et al., 1991; Piazza and Le Moal, 1996). This finding is consistent with the observation of Schenk et al. (1991) that reduction of dopaminergic tone in the mPFC by 6-OHDA lesions facilitates acquisition of cocaine IV self-administration. The role of the mPFC in behavioral inhibition may also be related to the presumed role of the mPFC in drug addiction. As will be outlined in section 3.3 repeated intake of drugs of abuse can alter mPFC function. Jentsch and Taylor (1999) have elaborated in a recent review that chronic drug (ab)use may result in prefrontal cortical cognitive deficits such that inappropriate unconditioned or conditioned responses to drugs, drug-related stimuli or internal drives can no longer be inhibited. From this results an excessive control over behavior by drugs or drug cues that results in craving and compulsive drug-seeking and drug-taking that cannot be suppressed or controlled by the addicted individual. Such loss of inhibitory control or increased ‘impulsivity’ can also be observed in other cases where prefrontal cortical function is disrupted, in particular in situations where it is required to shift behavioral responses away from one set of rules that have determined responding before to a new set of rules that determine responding in a different way (‘rule set shifting’). Such deficits manifest themselves as increased perseveration in go/ no go and discrimination reversal learning tasks (Iversen and Mishkin, 1970; Rosenkilde, 1979; Milner, 1982; Robbins, 1990, 1996; Damasio, 1996; Dias et al., 1996a,b, 1997). Also, lesions of the mPFC in rats and monkeys impair the extinction of an operant response (Butter, 1968; Rosenkilde, 1979; Weissenborn et al., 1997) which can also be interpreted in terms of increased perseveration. In fact, cognitive decision-making and attention processes can be altered in chronic drug abusers (O’Malley et al., 1992; Rosselli and Ardila, 1996; McKetin and Mattick, 1998; Jentsch and Roth, 1999; Rogers et al., 1999). As outlined in section 3.3, repeated administration of drugs of abuse often causes a ‘tolerance’ to the DA-releasing effects of the drug in the mPFC. If prefrontal cortical DA is a crucial element in the mediation of behavioral inhibition by the mPFC, then it is obvious how repeated intake of drugs of abuse could lead to loss of inhibitory control. Jentsch and colleagues (Jentsch et al., 1997a,b, 1998b,c,d, 1999) have shown that long-term exposure to PCP also causes a hypodopaminergic state in the prefrontal cortex. Interestingly, in these studies a good correlation was found between the degree of DA hypofunction and the degree of
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cognitive impairment (in terms of perseverative behavior and response inhibition deficits). Taken together, these observations suggest that by virtue of its role in behavioral inhibition, disturbances in mPFC function may not only be involved in psychiatric diseases but may also be an important factor in the etiology of drug abuse and addiction. It has been shown that spontaneous or precipitated withdrawal from several drugs of abuse after chronic administration causes a decrease in basal extracellular levels of DA in the NAS (Acquas et al., 1991; Parsons et al., 1991; Pothos et al., 1991; Robertson et al., 1991; Acquas and Di Chiara, 1992; Imperato et al., 1992a; Rossetti et al., 1992; Weiss et al., 1992; Crippens and Robinson, 1994; Spanagel et al., 1994; Hildebrand et al., 1998). In contrast to this, spontaneous and naloxone-precipitated withdrawal from morphine produced clear increases in extracellular levels of DA in the mPFC (Bassareo et al., 1995) while mecamylamine-induced withdrawal from chronic nicotine treatment did not significantly affect DA in the mPFC (Hildebrand et al., 1998). Unfortunately, to our knowledge only little further information exists concerning the effects of withdrawal from other drugs of abuse on DA in the mPFC. Dworkin and Smith (1992) reported that 24 h of withdrawal from self-administered cocaine had no effect on DA turnover rate in the frontal cortex but decreased serotonin turnover in this brain region. It is, however, difficult to compare these data to those of Bassareo et al. (1995) since the data from the self-administering animals was compared to that of yoked controls. Thus, these data would show differential effects of withdrawal from contingent versus non-contingent cocaine but not effects of withdrawal from cocaine as such. Nevertheless, the finding for morphine suggests that mesoaccumbal and mesocortical dopaminergic neurons are affected in an opposite way during withdrawal. Since withdrawal from a chronically administered drug of abuse certainly is experienced as a stressful situation, this increase in extracellular DA levels in the mPFC is consistent with the high responsiveness of the mesocortical projection to stress (see section 2.2.2).
3.2. Motor beha6ior 3.2.1. Effects of intra-mPFC drug injections Amphetamine injections into the mPFC were found to reduce hyperlocomotion induced by intra-NAS injections of amphetamine without producing an effect on locomotion by itself (Vezina et al., 1991; Hooks et al., 1992; Tassin et al., 1992). However, intra-mPFC injections of amphetamine were also reported to produce moderate increases in open-field activity, although the effects were much weaker compared to those obtained by injection of amphetamine into the NAS (Dougherty
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and Ellinwood, 1981; Carr and White, 1987; Kelley et al., 1989). Intra-mPFC injection of the D1 receptor antagonist SCH23390 (but not of the D2 receptor antagonist sulpiride) increased the locomotor-stimulatory effect of intra-NAS amphetamine while having no effect on locomotion by itself (Vezina et al., 1991, 1994; it should be mentioned here, however, that 2 days following the initial injections animals in the latter study actually showed an attenuated response to intraNAS injection of amphetamine, suggesting that even short-term D1 receptor blockade in the mPFC can have lasting effects on subcortical dopaminergic neurotransmission). Conversely, catalepsy induced by peripheral administration of haloperidol was potentiated by intramPFC injection of apomorphine which, by itself, had no effect on catalepsy scores (Bubser and Schmidt, 1994). Very surprisingly, Tucci et al. (1994) reported that intra-mPFC injections of DA clearly reduced the catalepsy produced by systemically administered haloperidol, a finding which is clearly incompatible with most other results. Apomorphine or amphetamine injections into the mPFC were also found to decrease spontaneous and amphetamine-induced open-field activity (Broersen et al., 1999; Lacroix et al., 2000). Injection of the specific DA reuptake inhibitor GBR 12909 into the mPFC also reduced novelty-induced locomotor activity, an effect that was attenuated by co-injection of a D1 or a D2 receptor antagonist, suggesting that the inhibitory effects of increased mPFC DA levels were mediated via both receptor subtypes (Radcliffe and Erwin, 1996). On the other hand, injection of the D2 receptor antagonist cis-flupenthixol into the mPFC failed affect the locomotor response to systemic amphetamine (Lacroix et al., 2000). Further evidence for the ‘inverse’ relationship of mPFC DA transmission and locomotor activity was presented recently by Hedou et al. (1999) who found a significant negative correlation between DA levels in the mPFC and locomotor activity (but a significant positive correlation between DA in the NAS and locomotor activity) after systemic administration of cocaine. Vice versa, locomotor hyperactivity was found to be positively correlated to the degree of DA depletion in the mPFC induced by lesioning the VTA or dopaminergic afferents of the mPFC (Tassin et al., 1978b). However, conflicting results come from a report by Klockgether et al. (1988) who found that intra-mPFC injection of the DA antagonist haloperidol produced catalepsy (much like intra-NAS or intrastriatal injections of haloperidol also produce catalepsy (Ellenbroek et al., 1985; Meyer et al., 1993)) and from a series of studies by Beninger and collegues on the effects of intra-mPFC injections of DA agonist and antagonist drugs on circling behavior (Morency et al., 1985, 1987; Stewart et al., 1985; Beninger et al., 1990). Based on their results these authors concluded that prefrontal
cortical DA, via a predominant action on D2 receptors, exerts a stimulatory influence on locomotor behavior. It is difficult to explain these findings along the same lines as the findings for excitotoxic lesions of the mPFC (see below) since alterations in postsynaptic DA receptor functions seem very unlikely given the fact that drugs were injected acutely into the mPFC. The reason for these discrepant findings remains unclear. Evidence for a role of the mPFC in the conditioned locomotor effects of amphetamine was presented by Mead et al. (1999) who found that pairing of a specific environment and amphetamine resulted in subsequent conditioned locomotion and c-fos expression in the mPFC upon exposure to that environment without prior drug administration. The AMPA/kainate receptor antagonist NBQX blocked the expression of the conditioned activity as well as the increase in mPFC c-fos expression, suggesting that AMPA receptors in the mPFC may participate in the mediation of amphetamine’s conditioned locomotor effects. Finally, Ikemoto and Goeders (2000) have shown that intra-mPFC injection of the muscarinic cholinergic antagonist scopolamine increased locomotor activity. However, such injections also attenuated the locomotor activity induced by systemic administration of cocaine, suggesting a rather complex role for cholinergic regulation of spontaneous and drug-induced locomotor activity.
3.2.2. Effects of mPFC lesions 3.2.2.1. 6 -OHDA lesions. In contrast to DA depletions in the NAS, the effects of DA depletions in the mPFC on motor behavior have been somewhat inconsistent. It has been shown early on and many times subsequently that 6-OHDA lesions of the NAS attenuate the behavioral effects of amphetamine and other indirect DA agonists (Kelly et al., 1975; Joyce et al., 1983), produce at least a transient decrease in spontaneous activity (Joyce et al., 1983) but increase the effects of direct DA agonists (Kelly et al., 1975; Joyce et al., 1983) presumably by inducing denervation supersensitivity of postsynaptic DA receptors in the NAS. The findings for 6-OHDA lesions in the mPFC on locomotor activity have been more variable. No effects on spontaneous and/or DA agonist-induced activity (Joyce et al., 1983; Oades et al., 1986; Clarke et al., 1988; Hemby et al., 1992b; Burns et al., 1993; Banks and Gratton, 1995), reduced spontaneous and/or DA agonist-induced activity (Sokolowski and Salamone, 1994; King and Finlay, 1995; Espejo, 1997; King et al., 1997) and enhanced spontaneous and/or DA agonist-induced activity (Carter and Pycock, 1980; Pycock et al., 1980b; Robinson and Stitt, 1981; Joyce et al., 1983; Bubser and Schmidt, 1990; Vezina et al., 1991; Duvauchelle et al., 1992; Jones and Robbins, 1992; Beyer and Steketee,
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1999) have all been reported. Due to the particularities of the mesocortical DA projection the outcome of a 6-OHDA lesion in the mPFC may depend much more on the exact degree of DA depletion than in the NAS. In addition, noradrenergic innervation, which is also affected by 6-OHDA, is much more prominent in the mPFC than in the NAS, which may introduce an additional potential source of variation for the effects of mPFC 6-OHDA lesions. Other points to consider in this context are the apparent functional heterogeneity of the mPFC (as outlined in more detail in section 4), and the possible development of denervation supersensitivity. Such effects have long been described for the striatum/NAS by the pioneers of this technique (Ungerstedt, 1971), and evidence exists that similar phenomena also occur in the mPFC (Haroutunian et al., 1988; Shibata et al., 1990, 1992).
3.2.2.2. Excitotoxic lesions. A potentiation of behaviors related to enhanced dopaminergic transmission in NAS and striatum following excitotoxic lesions of the mPFC has been reported. In early studies it was shown that relatively large excitotoxic or ablative lesions of the mPFC produce spontaneous locomotor hyperactivity (Richter and Hawkes, 1939; Lynch, 1970; Kolb, 1974a,b,c). Animals bearing more restricted ibotenic acid lesions of the mPFC showed attenuated haloperidol-induced catalepsy and enhanced apomorphine-induced stereotypy (Scatton et al., 1982; Worms et al., 1985; Braun et al., 1993; Jaskiw et al., 1993; Lipska et al., 1995), enhanced amphetamine-induced hyperactivity (Jaskiw et al., 1990a), (at least transiently) elevated levels of basal activity (Jaskiw et al., 1990a; Yee, 2000), and enhanced response to stress (Jaskiw et al., 1990b; Jaskiw and Weinberger, 1992). Consistent with these observations is the finding that TTX infusion into the mPFC (which would block the activity of corticofugal projections) also leads to an enhancement of dopaminergic transmission in the NAS (Louilot et al., 1989). However, as in the case of 6-OHDA lesions the findings for the effects of excitotoxic lesions on motor activity are not entirely consistent. Weissenborn et al. (1997) reported that quinolinic acid lesions of the mPFC enhanced locomotor activity in a novel environment but did not affect the locomotor-stimulant effects of cocaine. Likewise, Lacroix et al. (1998) found that NMDA lesions of the mPFC increased spontaneous activity in an open field but did not significantly affect the locomotor response to amphetamine. Wolf and Xue (1999) also reported that ibotenic acid lesions of the mPFC did not affect amphetamine-induced locomotor activity. Finally, Tzschentke and Schmidt (1999, 2000a) found no effects of small or large mPFC quinolinic acid lesions on spontaneous activity and on cocaine- and amphetamine-induced locomotor activity. In the study by Isaac et al. (1989) aspiration lesions of the mPFC
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did not affect spontaneous activity in the open field or in the running wheel. If one assumes that DA in the mPFC inhibits pyramidal cells and that glutamatergic corticofugal projections to the VTA (and/or to the PPTg) activate dopaminergic cells (see sections 2.3.1 and 2.3.2) it is surprising that excitotoxic and 6-OHDA lesions of the mPFC should have essentially the same effects on behaviors related to subcortical dopaminergic activity. While the explanation for the effects of 6-OHDA lesions, based on the above assumptions, is quite straightforward (removal of the inhibitory dopaminergic tone in the mPFC would ‘disinhibit’ glutamatergic excitatory projections to the VTA), the explanation for the effects of excitotoxic lesions is less clear. At first sight one would expect that the removal of the excitatory mPFC output to the VTA leads to a decrease in behaviors related to dopaminergic activity. The findings with apomorphine in particular, however, suggest that the observed effects (i.e. increase in behaviors related to dopaminergic activity) are due to alterations in postsynaptic DA receptors in the NAS/striatum. The removal of excitatory input to the VTA could initially lead to decreased DA input to subcortical sites which could then produce a ‘secondary’ denervation supersensitivity of DA receptors in postsynaptic NAS/striatum neurons. The observation that mPFC lesions increase spontaneous behavior might be related to the fact that mPFC lesions have also been shown to slow habituation to new situations or environments (Glaser and Griffin, 1962; Kolb, 1974c). Since in most studies examining spontaneous activity animals were transferred from their home cages to a presumably relatively novel test environment it is conceivable that reduced habituation can result in elevated levels of activity. Another aspect that should be kept in mind when discussing the effects of mPFC lesions on spontaneous activity is that impairing mPFC function may increase behavioral measures of anxiety or timidity, such as thigmotaxis in an open field or time spent on the closed arms of an elevated plus maze (Nonneman et al., 1974; Holson, 1986a,b; Jaskiw and Weinberger, 1990; Morgan and LeDoux, 1995; Jinks and McGregor, 1997). Thus, in particular, when locomotor activity of lesioned animals is tested under stressful conditions (e.g. in a novel environment or in large open fields), these anxiety or timidity effects may influence the expression of spontaneous behavior. If a reduction of such behavior is observed in mPFC-lesioned animals the possibility should be considered that this effect may not be a ‘genuine’ reduction in locomotor activity but may be the expression of anxiety-induced suppression of ongoing behavior.
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3.3. Beha6ioral sensitization The mPFC is not only involved in the mediation of the acute effects of drugs but also in the mediation of the long-term consequences of repeated drug administration on neurochemistry and behavior. Although it remains to be determined whether the mPFC plays a role in the development of tolerance to drugs, there is good evidence that the mPFC is involved in at least some forms of sensitization and that the repeated administration of drugs can lead to changes in prefrontal cortical neurotransmission. The term ‘behavioral sensitization’ refers to the progressive increase in the behavioral response (in most cases measured as locomotion or stereotypic behaviors) to the repeated administration of a constant drug dose. The interest in the mPFC in the context of sensitization has increased because of the suggestion that glutamatergic inputs to the VTA are an essential element in the circuitry mediating the initiation of sensitization (Sorg and Kalivas, 1993b; Perugini and Vezina, 1994; Cador et al., 1995; Kalivas, 1995, for details about the circuitry and mechanisms thought to be involved in sensitization). Evidence for a possible causal relationship between drug-induced release of glutamate in the VTA and sensitization, and the importance of the mPFC as a source of glutamate in the VTA, was provided by Wolf and Xue (1999) who showed that those treatments that have been shown to block the development of amphetamine sensitization also block the amphetamine-induced increase in VTA glutamate release (i.e. treatment with MK-801 or SCH23390 (Wolf and Xue, 1999), excitotoxic lesions of the mPFC (see Wolf, 1998; but see discussion below for conflicting findings concerning mPFC lesion effects on the development and expression of sensitization)). Also, D1 receptors are located on the terminals of glutamatergic fibers originating from the mPFC (Dewar et al., 1997; Lu et al., 1997b), although the relation of activation of these presynaptic D1 receptors and the increase in extracellular glutamate may not be trivial since in other brain areas such presynaptic D1 receptors have been shown to have inhibitory rather than facilitatory effects on transmitter release and neuronal excitation (Pennartz et al., 1992; Momiyama et al., 1996; Nicola et al., 1996; Nicola and Malenka, 1997). In addition, presynaptic D1 receptors in the VTA are also located on GABAergic terminals where they facilitate GABA release (Cameron and Williams, 1993). Thus, the mechanisms at the level of the VTA involved in the initiation of sensitization may be more complex than a ‘simple’ feed-forward loop between symatodendritic DA and D1 receptors on glutamatergic terminals.
3.3.1. Alterations in DA release during repeated drug administration A single administration of amphetamine has been shown to induce persistent, time-dependent behavioral as well as neurochemical sensitization. Interestingly, while the effects of a challenge injection of amphetamine on locomotion and DA release in the NAS became progressively stronger with increasing withdrawal duration, the effects on mPFC DA release decreased with prolonged withdrawal (Vanderschuren et al., 1999). This is consistent with the notion that prefrontal DA functionally antagonizes the effects of psychostimulants and other drugs on locomotion and NAS DA release (Louilot et al., 1989; Vezina et al., 1991; see discussion in section 3.2) such that a tolerance to the drug effect in the mPFC might contribute to the emergence of sensitization to the drug effect on DA release in the NAS and on the behavioral level (Banks and Gratton, 1995; Prasad et al., 1999). Long-term treatment with cocaine was also reported to induce a longlasting (\ 6 weeks) decrease in basal DA turnover in the mPFC but not in the NAS and striatum, where the reduction in DA turnover was only a transient effect (B 1 week) (Karoum et al., 1990). The potential importance of ‘tolerance’ to the DA-releasing effects of drugs in the mPFC for the emergence (i.e. ‘disinhibition’) of sensitization is also suggested by several other findings. As outlined in previous sections, stress can induce a clear DA release in the mPFC. This stress-induced mPFC DA release is strongly reduced in animals sensitized to cocaine, suggesting that a sensitizing drug treatment ‘blunts’ the DA response in the mPFC not only to the drug itself but also to other challenges (Sorg and Kalivas, 1993a,b). The reverse was also found, i.e. animals that had experienced repeated footshock stress did not show a sensitized DA release in the mPFC in response to an acute cocaine challenge (although they did show a sensitized DA response in the NAS) (Sorg, 1992). The observed tolerance to cocaine’s DA-releasing effects in the mPFC was not due to altered releasability of DA from mesocortical terminals nor to altered response of prefrontal cortical DA terminals to the local effects of cocaine (Sorg et al., 1997). A tolerance to the DA-releasing effects of morphine in the mPFC (with a concurrent increase in DA release in the NAS) with repeated, sensitizing treatment has also been reported (Tassin et al., 1992; Vezina et al., 1992), and a similar decrease of effect of repeated treatment with ketamine or PCP on extracellular levels of mPFC DA (with a concurrent increase in basal DA levels in the mPFC) was found as well (Jentsch et al., 1997a,b, 1998b; Lindefors et al., 1997). Furthermore, a similar effect (i.e. tolerance to the DA-releasing effects in the mPFC) was found for repeated administration of delta-9-tetrahydrocannabinol (THC) (Jentsch et al.,
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1998a). Finally, a tolerance to the effects of amphetamine on the mPFC with repeated treatment was observed not only with respect to DA transmission (see above) but also with respect to c-fos expression in the mPFC induced by amphetamine, although the latter effect may well be a consequence of the former effect, since co-treatment with a D4 receptor antagonist blocked the induction of c-fos expression by acute amphetamine treatment (Feldpausch et al., 1998). Interestingly, White et al. (1995a) presented evidence that with repeated cocaine administration the inhibitory response of pyramidal cells to DA also decreased, i.e. the decrease of inhibitory effects of DA on mPFC efferents in the course of sensitization may be related not only to a reduction in the amount of DA released but also to a reduced capacity of the released DA to induce inhibition of postsynaptic cells. It should be noted, however, that this ‘blunting’ or ‘disinhibition’ may not be a universal mechanism responsible for the development of sensitization to all drugs that have been found to induce behavioral sensitization. For example, a rather opposite effect has been found in the course of the development of nicotine sensitization, i.e. no effect or even a reduction in subcortical dopaminergic activity but an increase in prefrontal cortical DA utilization and release, and an increase in prefrontal cortical Fos expression by repeated, sensitizing treatment with nicotine (Vezina et al., 1992; Nisell et al., 1996, 1997). Others have shown that amphetamine sensitization can be associated with a sensitized DA response in both structures (Robinson et al., 1988; Stephans and Yamamoto, 1995). As mentioned above, a tolerance to the DA-releasing effects in the mPFC of a cocaine-challenge in stress-preexposed animals and also the reverse, i.e. a tolerance to the DA-releasing effects in the mPFC of an acute exposure to stress in cocaine-pretreated animals has been found (Sorg and Kalivas, 1993a). On the other hand, Hamamura and Fibiger (1993) reported that exposing amphetamine-sensitized rats to stress did produce a sensitized DA response in the mPFC, although the mPFC DA response to an amphetamine challenge was not different in sensitized and control animals. This would suggest that prefrontal DA is involved in crosssensitization between amphetamine and stress but not in amphetamine-induced sensitization as such. Furthermore, in animals sensitized by repeated injections of methamphetamine, potassium-evoked release of DA in the mPFC (but not in the striatum) was enhanced compared to control animals, and methamphetamineinduced DA release in the mPFC (but not in the striatum) was also greater in methamphetamine-pretreated animals (Stephans and Yamamoto, 1995). The finding of Sorg et al. (1997) that intra-cortical administration of cocaine did not mimic the effect of systemically administered cocaine in sensitized animals
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(i.e. unlike systemic cocaine, locally applied cocaine still produced a sensitized DA response within the mPFC) suggests that this tolerance is not due to local changes within the mPFC but rather due to changes in the regulation of mesocortical neurons at the level of the VTA. To our knowledge, it has not been systematically examined yet whether mesocortical DA neurons in cocaine- or morphine- versus amphetamine- or nicotine-sensitized animals would respond differentially to synaptic inputs at the level of the VTA or whether these synaptic inputs (i.e. afferent regulation of the VTA; see Kalivas, 1993) themselves would be differentially altered in cocaine- or morphine- versus amphetamine- or nicotine-sensitized animals. As in the case of psychomotor stimulants, chronic administration of neuroleptic drugs has also been shown to cause differential alterations in dopaminergic activity in mPFC and NAS/striatum. Thus, acute administration of a neuroleptic drug increases dopaminergic activity (synthesis, metabolism, release) in both mPFC and NAS/striatum (Carlsson and Lindqvist, 1963; Scatton et al., 1976; Scatton, 1977; Matsumoto et al., 1983; Moghaddam and Bunney, 1990). However, chronic treatment is associated with an attenuation (i.e. tolerance) of this increase in dopaminergic activity in the NAS/striatum but not or only to a much lesser degree in the mPFC (Scatton et al., 1976; Scatton, 1977; Bacopoulos et al., 1978, 1979, 1980, 1982; Nicolaou, 1980; Bannon et al., 1982, 1983; Bowers and Hoffman, 1986; Moghaddam and Bunney, 1990; but see Chang et al., 1989; Essig and Kilpatrick, 1991). An alternative way to interpret these data is to acknowledge that repeated neuroleptic administration can result in depolarization inactivation in midbrain dopaminergic neurons (Bunney and Grace, 1978; Chiodo and Bunney, 1983; White and Wang, 1983). Interestingly, Chiodo and Bunney (1983) found that after induction of depolarization inactivation in most VTA neurons, the majority of neurons that were still active projected to the mPFC. Thus, the apparent tolerance to the stimulatory effects of neuroleptics on dopaminergic activity in the NAS/striatum may be due to the emergence of depolarization inactivation with prolonged treatment, and the observed lack of tolerance to these effects in the mPFC may be related to the fact that mesocortical DA neurons are not driven into depolarization inactivation to the same degree by the neuroleptic treatment. In summary, the role of the mPFC in sensitization mechanisms, as established so far, is presumed to be twofold. Firstly, prefrontal cortical efferents to the VTA are thought to provide important glutamatergic input to DA neurons, which, acting via NMDA receptors, provides a crucial signal for the initiation of sensitization. The tolerance to the DA-releasing effects in the mPFC of at least certain sensitizing drugs that develops with repeated treatment might be one mecha-
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nism which enhances the glutamatergic signal in the VTA over time by reducing dopaminergic inhibition of mPFC pyramidal cells projecting to the VTA. Thus, via its projections to the VTA the mPFC is thought to be involved in the initiation of sensitization. Secondly, prefrontal cortical efferents to the NAS are thought to provide important glutamatergic input to spiny neurons, which, acting via AMPA receptors, provides a crucial signal for the expression of sensitization. The enhanced glutamatergic transmission in the NAS might also be due to reduced dopaminergic inhibition within the mPFC. A more detailed consideration of the mechanisms thought to underlie the development and expression of sensitization is beyond the scope of this review, but the reader is referred to a number of several further reviews that cover this topic in detail (Kalivas and Stewart, 1991; Sorg and Kalivas, 1993b; Wise and Leeb, 1993; Kalivas, 1995; White, 1996; Pierce and Kalivas, 1997; Wolf, 1998).
3.3.2. Lesion effects Studies using excitotoxic lesions of the mPFC have produced conflicting findings on the role of the mPFC in the development and expression of sensitization induced by amphetamine and cocaine. For amphetamineinduced sensitization it was reported that ibotenic acid lesions of the mPFC blocked the development of locomotor sensitization induced by repeated low dose systemic or intra-VTA administration of amphetamine (Cador et al., 1999) and also the development of sensitization of post-stereotypy hyperlocomotion (but not sensitization of stereotypy itself) induced by repeated systemic administration of high doses of amphetamine (Wolf et al., 1995). On the other hand, no effect of quinolinic acid lesions of the mPFC on the development of amphetamine-induced sensitization has also been reported (Tzschentke and Schmidt, 1998a,b), and the expression of amphetamine sensitization was found to be unaffected by ibotenic acid lesions when lesions were made after sensitization was established (Li and Wolf, 1997). The reported lack of effect of mPFC lesions on amphetamine-induced sensitization is compatible with the findings of Clarke et al. (1988) who showed that 6-OHDA lesions of the NAS but not of the mPFC reduced the acute locomotor response to amphetamine. This finding also argues for a relative independence of amphetamine effects from the mPFC and, in particular, of dopaminergic transmission in the mPFC. This is consistent with the observation that single or even repeated intra-mPFC infusions of amphetamine do not affect spontaneous locomotor activity and the locomotion induced by acute systemic injection of amphetamine, cocaine or caffeine (Hooks et al., 1992; Ben-Shahar and Ettenberg, 1998).
With respect to cocaine-induced sensitization the picture is equally inconsistent. While Tzschentke and Schmidt (1998c,a,b) and Li et al. (1999b) reported that the development of sensitization on the behavioral and cellular level was blocked by excitotoxic lesions of the mPFC, Weissenborn et al. (1997) found no effect of on the development of cocaine-induced sensitization. As regards the expression of cocaine-induced sensitization, no effect of mPFC lesions was found in one study (Li et al., 1999a) while lesions of the dorsal (but not of the ventral) mPFC blocked the expression of the sensitized behavioral response to cocaine in another study (Pierce et al., 1998). We have recently found that quinolinic acid lesions of the mPFC blocked the expression of morphine-induced behavioral sensitization but not the expression of sensitization induced by MK-801 (Tzschentke and Schmidt, 2000b). The reason for these discrepancies is not clear, but it may be that they are due to procedural differences since different neurotoxins, toxin infusion sites, drug doses, treatment and test protocols were used and different behavioral measures were taken in the above-mentioned studies. Interestingly, Banks and Gratton (1995) reported that 6-OHDA lesions of the mPFC while attenuating the acute response to amphetamine actually enhanced sensitization produced by subsequent repeated systemic amphetamine injections on the behavioral (i.e. locomotor activity) as well as on the neurochemical (i.e. DA release in the NAS) level. This observation is nicely complemented by the finding that intra-mPFC infusions of amphetamine together with peripheral amphetamine injections can attenuate the development of sensitization (Ben-Shahar and Ettenberg, 1998). In this case, amphetamine administered into the mPFC would ‘compensate’ for the tolerance in the DA response developing to the peripheral amphetamine administration and would keep DA concentrations at a high level during each peripheral injection of the drug (Maisonneuve et al., 1990). Interestingly, the data from this latter study suggested that intra-mPFC infusions of amphetamine blocked the ‘pharmacological’, i.e. context-independent aspects of sensitization but did not affect the ‘conditioned’, i.e. context-dependent aspects of sensitization. The inhibitory effects of prefrontal DA on sensitization processes does not seem to be specific to sensitization induced by pharmacological agents but is also seen in cases where sensitization effects are induced by repeated exposure to naturally reinforcing stimuli. Thus, Mitchell and Gratton (1992) found that partial mPFC DA depletions enhanced the development of sensitization to the NAS DA releasing effects of sexual stimuli.
3.3.3. Possible differential role of the mPFC in cocaine- 6ersus amphetamine-induced sensitization From the data reviewed in the preceding sections it is
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obvious not only that the findings concerning the role of the mPFC in reward- and sensitization-related processes in general are rather inconsistent, but also that, in particular, striking differences seem to exist with respect to the role of the mPFC between cocaine and amphetamine sensitization. The reason for these differences is not known. It is interesting to note, however, that there are a number of differences in the effects of both drugs that relate to the mPFC in one way or another. For example, it has been shown that both drugs differentially affect firing of mesocortical neurons. Thus, while both drugs inhibit firing of mesoaccumbal neurons (White et al., 1987; Einhorn et al., 1988), only amphetamine inhibits firing of mesocortical neurons while cocaine fails to do so (Wang, 1981; Chiodo et al., 1984; White et al., 1987). Furthermore, while amphetamine exerts its effects relatively selectively on dopaminergic neurons, cocaine, in addition to its blockade of the DA transporter, also has prominent direct effects on other neurons as well. Cocaine also blocks with high affinity the NA and 5-HT transporters (Reith et al., 1986, 1997). Given the complex mutual pre- and postsynaptic interactions within the mPFC between these monoamines, it may not be surprising that cocaine and amphetamine can have quite different effects with respect to mPFC function. Of particular relevance may be the fact that the NA transporter significantly contributes to the removal of DA from the synaptic cleft in the mPFC (see section 2.2.4). DA released by amphetamine could thus still be removed from the synaptic cleft by the NA transporter while this mechanisms of DA inactivation would not be available in the cocaine-treated animal due to the concurrent blockade of DA as well as NA transporters by cocaine. One basic difference between amphetamine and cocaine with respect to their effect on extracellular DA levels is that the effect of amphetamine is at least partly impulse-independent while the effect of cocaine is impulse-dependent (Benwell et al., 1993; Kuczenski and Segal, 1994). Since mesocortical DA neurons have a higher rate of impulse-flow (higher firing rate and higher rate of DA release) than other DA neurons, cocaine may be particularly potent in exerting its effects in the mPFC relative to subcortical sites while amphetamine would affect all DA neurons in a similar fashion independently of their activity level. Therefore, the mPFC might play a relatively more important role in the mediation of cocaine-induced behavioural effects, including sensitization. At the subcortical level, additional differences between cocaine and amphetamine effects after acute and, in particular, chronic administration have also been observed. Evidence that the mPFC may be more important for cocaine-induced sensitization than for amphetamine-induced sensitization comes from microdialysis studies measuring extracellular levels of
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glutamate in the NAS during a challenge with the respective sensitizing drug after a sensitization has been established. Thus, cocaine-sensitized rats release more glutamate in the NAS (core) than non-sensitized rats in response to a cocaine challenge, an effect that was blocked by ibotenic acid lesions of the dorsal mPFC (Pierce et al., 1998). In contrast, no difference was found between amphetamine-sensitized and non-sensitized rats in response to an amphetamine challenge (Xue et al., 1996). After withdrawal from chronic amphetamine treatment, a decrease in the levels of GluR1 and GluR2 receptor subunits and their respective mRNA was observed in the NAS (Lu et al., 1997a; Lu and Wolf, 1999). In contrast, no such decrease was observed after withdrawal from chronic cocaine (if anything, there was a strong trend towards an elevation of the levels of GluR1 mRNA (Ghasemzadeh et al., 1999). Furthermore, the cocaine-induced increase in extracellular glutamate levels in the NAS was augmented by repeated cocaine injections (Pierce et al., 1996; Reid and Berger, 1996) while the delayed increase in NAS glutamate levels produced by amphetamine was not altered during repeated amphetamine treatments (Xue et al., 1996). Thus, it is not only the function of the mPFC that is differentially affected by cocaine and amphetamine, but also other central structures of the mesocorticolimbic circuit. In fact, these latter findings for NAS glutamate release nicely fit into the general picture. As mentioned above, cocaine — but not amphetamine — induced DA release in the mPFC shows tolerance with repeated drug administration. If one assumes that neuronal glutamate measured in the NAS is predominantly of prefrontal cortical origin, then the observed increase in glutamate after chronic cocaine, but not amphetamine, could directly be related to the diminished dopaminergic inhibition of corticofugal pyramidal cells in the mPFC. Although this scenario is speculative, it can easily be subjected to experimental testing, and the results from such studies could potentially make a considerable contribution to our understanding of sensitization in general and of the neurobiological mechanisms underlying the differences between cocaine and amphetamine in particular. A number of other approaches have been used to examine the role of the mPFC in amphetamine and cocaine sensitization. Firstly, electrical kindling of the mPFC produced sensitization to the locomotor activating effects of cocaine (Schenk and Snow, 1994). In the light of the above-mentioned apparent differences with respect to the role of the mPFC for cocaine- and amphetamine-induced sensitization, it would be interesting to determine whether such a kindling regimen of the mPFC would also sensitize animals to the locomotor-activating effects of amphetamine. Since such an
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effect was already demonstrated for amygdala kindling (Kirkby and Kokkinidis, 1987; Gelowitz and Kokkinidis, 1993) and since repeated amphetamine administration has been shown to produce an increase of DA release in the amygdala (Harmer et al., 1997; Harmer and Phillips, 1999) it may be well worth to further explore the role of the mesoamygdaloid DA projection in amphetamine sensitization. Secondly, a behaviorally sensitizing regimen of repeated amphetamine administrations has been shown to alter the reactivity of VTA DA neurons to electrical stimulation of the mPFC, such that mPFC stimulation produced bursts in VTA DA neurons on a greater number of trials after short (i.e. 2-day) withdrawal, and that VTA DA neurons showed a greater relative percentage of purely excitatory responses compared to inhibitory/excitatory responses after mPFC stimulation after longer (i.e. 10-day) withdrawal. In other words, in amphetamine-sensitized animals electrical stimulation of the mPFC produced an overall greater stimulation of midbrain dopaminergic cells than in control rats (Tong et al., 1995; Clark and Overton, 1998). Although it is not possible to decide on the basis of these results whether the observed effects are due to enhanced responsiveness of the mPFC to the applied electrical stimulation or to enhanced responsiveness of DA neurons to a given excitatory input, it is nevertheless possible that the observed effects are due only to the latter, i.e. the effects produced by chronic amphetamine could be entirely mediated at the level of the VTA, in the absence of any alterations within the mPFC. This interpretation is supported by the observation that chronic amphetamine or cocaine administration increases the expression of the NMDA receptor subunit NMDAR1 and the AMPA receptor subunit GluR1 in the VTA (Fitzgerald et al., 1996), and that after chronic amphetamine or cocaine administration VTA DA neurons are more sensitive to iontophoretically applied glutamate, in that they more readily enter a state of apparent depolarization blockade (White et al., 1995b). It should be mentioned, however, that an increase in the expression of GluR1 subunits and a decrease in the expression of NMDAR1 subunits and their corresponding mRNA has also been observed in the mPFC following withdrawal from chronic amphetamine treatment, indicating that alterations intrinsic to the mPFC may also be involved in the chronic actions of amphetamine (Lu et al., 1997a, 1999a,b; Lu and Wolf, 1999). Unfortunately, from the results of the latter studies it is difficult to determine whether the changes in receptor subunit expression occurred in pyramidal cells or interneurons or both, although the available data suggests that, at least in the case of NMDAR1, the relevant receptors may be located on pyramidal neurons (Conti et al., 1994; Petralia et al., 1994a,b; Rudolf et al., 1996). A further complicating factor (which in
fact applies to many other sensitization experiments as well) is that the respective alterations were observed only after a period of withdrawal from repeated drug treatment. Thus, it is often not clear whether the observed adaptations were produced by the repeated drug treatment per se or by alterations induced by the withdrawal. This point is nicely demonstrated by the findings of Onn and Grace (2000) who showed, using a combination of electrophysiological and anatomical techniques, that repeated amphetamine injections can alter the electrophysiological and structural characteristics of mPFC pyramidal cells as well as of NAS spiny neurons. It was shown that after 7 or more days of withdrawal from repeated amphetamine there was an increased incidence of dye coupling in both neuron populations. Furthermore, a larger proportion of prefrontal pyramidal cells showed burst activity, and a larger proportion of both cortical pyramidal cells and NAS spiny neurons showed bistable membrane oscillations. Notably, none of these changes were observed when measurements were taken during the treatment period. Thirdly, structural changes have been observed in both the mPFC and the NAS following a sensitizing treatment with amphetamine, cocaine, or morphine (Robinson and Kolb, 1997, 1999a,b). These findings show that repeated administration of amphetamine and other drugs can induce persistent changes in the mPFC. What is not clear, however, from these data is the extent to which these alterations are of relevance for the manifestation of the observed behavioral and neurochemical effects. In other words, it is not known whether these changes are causally related to the observed effects or whether they are mere accompanying phenomena without a causal relationship to the observed behavioral and neurochemical effects. Taken together, while comprehensive evidence suggests that behavioral sensitization to amphetamine and cocaine (as well as other drugs of abuse) is closely and positively linked to an increase in DA release in the NAS/striatum (Robinson and Becker, 1986; Robinson et al., 1988; Kazahaya et al., 1989; Akimoto et al., 1990; Kalivas and Duffy, 1990; Petit et al., 1990; Hamamura et al., 1991; Patrick et al., 1991), the situation for the role of mPFC DA release is much less clear and may depend on the behavioral procedure employed and, in particular, on the type of drug used to produce sensitization. The findings reviewed in this section suggest that it would be too simple to state that the mPFC is or is not involved in sensitization processes. One clearly has to distinguish between different drugs, the sensitization to which may depend to a differential degree on mPFC function. One also has to differentiate between the role of the dopaminergic innervation of the mPFC in sensitization processes and functions of the mPFC which are not directly related to dopaminergic
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mechanisms but which may nevertheless be important for the development or expression of sensitization to different drugs.
3.4. Schizophrenia and cognition One of the most long-standing assertions about the function of the prefrontal cortex is that it is importantly involved in cognitive processes such as attention, response selection and inhibition, spatial learning, temporal sequencing of actions, planning of forthcoming behavior based on previously acquired information, and working memory. These functions have been inferred from deficits in paradigms such as delayed alternation, delayed non-matching-to-position, delayed non-matching-to-sample, reversal learning, go/no-go alternation, and various maze (Y, radial-arm, water maze) and attention tasks in experimental animals or deficits in the Wisconsin Card Sort task in humans, caused by lesions or pharmacological disruption of the prefrontal cortex (see e.g. Milner, 1963; Brozoski et al., 1979; Fuster, 1980; Simon et al., 1980; Simon, 1981; Kolb et al., 1983; Kolb, 1984; Milner and Petrides, 1984; Sakurai and Sugimoto, 1985; Doar et al., 1987; Wolf et al., 1987; Olton et al., 1988; van Haaren et al., 1988; Stam et al., 1989; Bubser and Schmidt, 1990; Goldman-Rakic, 1990; Poucet, 1990; Wilcott and Xuemei, 1990; McCarthy et al., 1994; Sokolowski and Salamone, 1994; Broersen et al., 1995; Granon et al., 1995; Seamans et al., 1995b; Murphy et al., 1996a; Muir et al., 1996; Bussey et al., 1997b; Schultz et al., 1998; Broersen and Uylings, 1999; Delatour and Gisquet-Verrier, 1999; Floresco et al., 1999; Ragozzino et al., 1999). One of the most prominent views about the overall function of the prefrontal cortex is that ‘‘… it functions to provide flexibility and unity in behavior by providing a kind of temporal structure in which behavior is organized over time into a meaningful whole’’. (Kolb, 1984, p.89; see also Fuster, 1980).
3.4.1. Dopamine and glutamate hypotheses Since many of the above-mentioned processes are disrupted in schizophrenia, prefrontal dysfunction, and in particular dysfunction of the dopaminergic innervation of the mPFC, is thought to be associated with the pathology of schizophrenia (Weinberger et al., 1986, 1988; Weinberger, 1987; Robbins, 1990; Deutch, 1992, 1993; Grace, 1991, 1992, 1993; Cummings, 1993; Lewis, 1995; Laruelle et al., 1996; Breier et al., 1997; Knable and Weinberger, 1997; Okubu et al., 1997; Akil et al., 1999; Laruelle and Abi-Dargham, 1999; Moore et al., 1999; Yang et al., 1999; Bertolino et al., 2000). This presumed association has spawned an enormous amount of research addressing the role of prefrontal cortical DA in these cognitive functions. It is important
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to mention, however, that another school of thought exists which posits that schizophrenia is not due to prefrontal dopaminergic dysfunction but rather to subcortical or cortical glutamatergic dysfunction (Kim et al., 1980; Javitt and Zukin, 1991; Schmidt, 1991; Sherman et al., 1991; Olney and Farber, 1995; Sams-Dodd, 1996; Steinpreis, 1996; Goff and Wine, 1997; HerescoLevy and Javitt, 1998; Jentsch and Roth, 1999; Bertolino et al., 2000; Glantz and Lewis, 2000). It is unclear if or how these two states relate to each other, given the strong interactions of both transmitter systems both cortically and subcortically. Nevertheless, systemically as well as at the level of the NAS/striatum DA and glutamate appear to have opposite effects on the activity of spiny neurons and on behavior (Carlsson and Carlsson, 1989a,b, 1990; Schmidt and Bubser, 1989; Elliott et al., 1990; Schmidt, 1991; Yukuro et al., 1991; Svensson and Carlsson, 1992; Ouagazzal et al., 1993; Iversen, 1995; Schmidt and Kretschmer, 1997). In line with this, it has been demonstrated that a stimulation of dopaminergic transmission as well as a blockade of glutamatergic transmission systemically or at the level of the NAS/striatum can produce psychotomimetic effects and cognitive disruption (Allen and Young, 1978; Sturgeon et al., 1979; Robinson and Becker, 1986; Schmidt, 1986; Burns and Lerner, 1976; McCullough and Salamone, 1992; Schmidt et al., 1992; Pierce and Rebec, 1993; Krystal et al., 1994; Ouagazzal et al., 1994; Steinpreis et al., 1994; Svensson et al., 1994a; Alkhatib et al., 1995; Carlezon and Wise, 1996a,b; Malhotra et al., 1996; Sams-Dodd, 1996; Verma and Moghaddam, 1996; Jentsch et al., 1997a,b). There is still some debate about the extent to which the effect of systemically administered glutamate antagonists is mediated indirectly via DA release in the NAS (Doherty et al., 1980; French, 1986a,b; Carboni et al., 1989; McCullough and Salamone, 1992; Steinpreis and Salamone, 1993; Jackson et al., 1994; Hertel et al., 1996). There is, however, evidence that the psychotomimetic and cognitive-disruptive effects of glutamate antagonists are at least partially independent of dopaminergic mechanisms (Keith et al., 1991; Carlsson and Carlsson, 1989a,b; Kitaichi et al., 1994; Ogawa et al., 1994; Ouagazzal et al., 1994; Ogren and Goldstein, 1994; Carlezon and Wise, 1996a; Druhan et al., 1996; Verma and Moghaddam, 1996; Waters et al., 1996; Adams and Moghaddam, 1998). In addition to the dopaminergic and glutamatergic systems, the prefrontal GABAergic system has also been implicated in schizophrenia (Simpson et al., 1989; Benes et al., 1991, 1992; Akbarian et al., 1995). But as in the case of the changes observed in prefrontal dopaminergic and glutamatergic transmission in schizophrenia, it is again not clear whether these alterations are the cause of the other observed changes and the symptomatology of schizophrenia or merely the
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(side-) effect of some other mechanism, be it dysfunction of the dopaminergic or glutamatergic system or another as yet unknown pathophysiological causal mechanism.
3.4.2. Prepulse inhibition The notion that schizophrenia involves a dysfunction of the mPFC (Weinberger, 1987) is also heavily based on findings from animal models of schizophrenia, in which mPFC lesions or intra-mPFC drug injections have been found to produce effects suggestive of schizophrenia-like symptoms. One of these animal models to assess sensorimotor gating mechanisms and information processing is prepulse inhibition (PPI) of the acoustic startle response in the rat (Braff and Geyer, 1990; Swerdlow et al., 1992a, 1994, 1995). PPI is the reduction of a startle response to an intense acoustic stimulus that is observed when this intense stimulus is preceded by a weaker, non-startling stimulus, or prepulse (Hoffman and Ison, 1980; Koch and Schnitzler, 1997; Swerdlow et al., 1992a; Swerdlow and Geyer, 1998; Koch, 1999). PPI is taken to model an organisms’ ability to ‘gate out’ or ‘filter out’ sensory and cognitive information, a process the disruption of which is considered to be an important feature in the symptomatology of schizophrenia (Nuechterlein and Dawson, 1984; Anscombe, 1987; Braff and Geyer, 1990). The interest in PPI as an animal model of schizophrenia arises mainly from the fact that PPI deficits can also be observed in schizophrenic patients (Braff et al., 1978, 1992; Swerdlow et al., 1994). Furthermore, PPI deficits can be induced by systemic administration of amphetamine or other DA agonists (Swerdlow et al., 1986; Koch, 1999) as well as PCP (Bakshi et al., 1994; Bakshi and Geyer, 1998), and the experimentally induced deficits as well as the deficits seen in schizophrenic patients can be reduced by neuroleptics (Bakshi et al., 1994; Koch and Bubser, 1994; Weike et al., 1999). DA in mPFC and NAS/striatum appears to have clear opposite roles with respect to its effects on PPI. Thus, drugs and treatments that decreased indices of dopaminergic activity in the mPFC have disruptive effects on PPI. For example, DA depletions by 6OHDA in the mPFC (Bubser and Koch, 1994; Koch and Bubser, 1994) and local mPFC injection of D1 and D2 receptor antagonists (Ellenbroek et al., 1996) were shown to disrupt PPI, while increases in dopaminergic activity in the mPFC had no effects on PPI (Swerdlow et al., 1986, 1990a,b, 1992b; but see Broersen et al. (1999) and Lacroix et al. (2000) who found that apomorphine injection into the mPFC disrupted PPI). Interestingly, systemic haloperidol treatment was able to reverse PPI deficits induced by 6-OHDA lesion of the mPFC (Koch and Bubser, 1994), and vice versa, intramPFC injection of haloperidol reversed PPI deficits induced by systemic apomorphine (Hart et al., 1998).
In contrast, various drugs and treatments that increase indices of dopaminergic activity in NAS or striatum have disruptive effects on PPI (Mansbach et al., 1988; Swerdlow et al., 1990a,b, 1992a; Wan and Swerdlow, 1993). Excitotoxic lesions of the mPFC that attenuate PPI (Yee, 2000) or that enhance the PPI-disrupting effects of low doses of apomorphine (Swerdlow et al., 1995) presumably do so via an increase in postsynaptic DA receptor sensitivity in subcortical areas (Jaskiw et al., 1990a; Braun et al., 1993), in analogy to what has been discussed above for the effects of such lesions on locomotion. This explanation may resolve the apparent paradox that 6-OHDA lesions of the mPFC (which presumably increase glutamatergic output from the mPFC) as well as excitotoxic lesions of the mPFC (which decrease glutamatergic output from the mPFC) produce increases in indices of dopaminergic activity, albeit apparently at two different levels. Thus, 6-OHDA lesions, by ‘disinhibiting’ excitatory input onto dopaminergic cells, increase subcortical measures of presynaptic DA activity (DA release, DA utilization) (Pycock et al., 1980b; Leccese and Lyness, 1987; Suzuki et al., 1995) and related behavioral measures (Robinson and Stitt, 1981; Joyce et al., 1983; Bubser and Schmidt, 1990; Jones and Robbins, 1992). On the other hand, excitotoxic lesions, by removing excitatory input onto dopaminergic cells, increases measures of postsynaptic DA activity (density, sensitivity and/or functional coupling of DA receptors) (Jaskiw et al., 1990a; Braun et al., 1993; Lipska et al., 1995; see also Christie et al., 1986) and related behavioral measures (Jaskiw et al., 1990a,b; Jaskiw and Weinberger, 1992; Braun et al., 1993; Lipska et al., 1995; see also Roberts et al., 1994; Wilkinson, 1997; Wilkinson et al., 1997). This increased postsynaptic dopaminergic activity does not seem to be due to an upregulation of the number or affinity of D1 or D2 receptors in the NAS or striatum (Jaskiw et al., 1991a) and may therefore involve changes in intracellular signalling and coupling of the receptors to second messenger systems (Mileson et al., 1991). In fact, a direct, antagonistic interaction between glutamatergic afferents and D1 receptor function in the striatum has been described (Reibaud et al., 1984; Halpain et al., 1990). Thus, removal of glutamatergic input to the striatum/NAS would relieve D1 receptor function from glutamate-mediated ‘inhibition’ and increase overall postsynaptic dopaminergic activity.
3.4.3. Latent inhibition Another example of behavioral inhibition processes is the phenomenon of latent inhibition (LI) where the repeated non-reinforced exposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement (Lubow, 1973; Lubow and Gewirtz, 1995). Thus, LI is considered to be an index of an organisms’ ability to ignore irrelevant stimuli, a
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process that is known to be disrupted in schizophrenia (Gray et al., 1991). As in the case of PPI, LI deficits can also be observed in acutely schizophrenic humans (Baruch et al., 1988; Gray et al., 1995; Lubow and Gewirtz, 1995), and these LI deficits can be modelled in experimental animals and in healthy humans by administration of amphetamine (Gray et al., 1992; Killcross et al., 1994; Thornton et al., 1996; Kumari et al., 1999); notably, in animal models the effects of systemic amphetamine are to a large extent mimicked by local infusions of the drug into the NAS (Solomon and Staton, 1982; Weiner et al., 1988; Kilcross and Robbins, 1993) and reversed by 6-OHDA lesions of the NAS and systemic or intra-NAS administration of haloperidol and other neuroleptic drugs (Weiner et al., 1990, 1996; Warburton et al., 1994; Gray et al., 1997). This suggests that LI deficits are primarily due to supra-normal DA transmission at the level of the NAS. In humans and animals neuroleptic treatment on its own potentiates LI effects, and it reverses LI deficits seen in schizophrenic patients (Weiner and Feldon, 1987; Christison et al., 1988; Feldon and Weiner, 1991; Williams et al., 1996; Trimble et al., 1997). It is interesting to note here, however, that the improvement of LI by neuroleptics is dose-dependent and that high doses of neuroleptics have been shown to disrupt rather than to enhance LI (Dunn et al., 1993; Kumari et al., 1999). This suggests that there may an optimal range of DA receptor activation for maximal LI and that deviation to below or above that range results in deficits in LI. This would be completely consistent with findings outlined in the next section that there appears to be an optimal and relatively narrow range of dopaminergic activity that is necessary for optimal cognitive performance. Interestingly, in contrast to the situation for PPI, in a search for the neural substrate of LI, no evidence for an involvement of the mPFC in LI mechanisms was found (Broersen et al., 1996; Ellenbroek et al. 1996; Joel et al., 1997; Lacroix et al., 1998, 2000). Thus, LI performance in rats was not affected by NMDA or electrolytic lesions of the mPFC, or injections of DA agonists and antagonists into that region. Rather, intact LI appears to depend on the integrity and normal functioning of the NAS and its inputs from the hippocampal formation and adjacent cortical areas (see Weiner, 1990; Weiner and Feldon, 1997, for review). Thus, it is somewhat difficult to reconcile the different lines of evidence in the context of LI as a model of schizophrenia. On the one hand, there is good evidence that LI has face validity and predictive validity as a model of schizophrenia, on the other hand the mPFC which is importantly involved in the etiology of schizophrenia does not seem to be part of the neuronal substrate mediating LI, questioning the construct validity of LI deficits as a model for schizophrenia.
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3.4.4. The relationship between dopaminergic tone and cogniti6e performance — the gating of information flow The potential role of the glutamatergic system nonwithstanding, the effects of mPFC DA on cognition appear to critically depend on the exact volume of dopaminergic transmission within a narrow range. Thus, an ‘inverted U-shape’ relationship between prefrontal cortical DA tone and cognitive performance has been described, with only some intermediate level of DA tone allowing for optimal performance while DA tones below or above that level disrupt performance (Brozoski et al., 1979; Sahakian et al., 1985; Sawaguchi and Goldman-Rakic, 1994; Murphy et al., 1996b; Zahrt et al., 1997; see Verma and Moghaddam (1996), Arnsten (1997) for further discussion). While in most of these aforementioned studies rather complex cognitive tasks in monkeys have been employed, in rat studies using the PPI and LI paradigms a rather similar picture of an optimal and narrow range of DA transmission for unimpaired cognitive performance has been delineated. Thus, in these paradigms it has also been found that enhancing as well as reducing DA in the mPFC can disrupt cognitive performance (see sections above). The particular relationship between dopaminergic tone and cognitive performance is also elegantly been demonstrated in a recent study by Granon et al. (2000). Here, rats were trained in a five-choice serial reaction time task. Subsequently, rats were divided into a group that achieved high baseline levels of accurate responding and into a group that achieved only low levels of accurate baseline responding. When the D1 receptor antagonist SCH23390 was infused into the prelimbic mPFC it was found that this drug selectively impaired the accuracy of attention performance in rats with high levels of baseline accuracy while having little effect in the group with low levels of baseline accuracy. Conversely, infusion of the D1 receptor agonist SKF38393 enhanced accuracy of attention performance in the low baseline group while having little effect in the high baseline group. Thus, the cognitive effects of DA (D1) agonists or antagonists in the mPFC depend on the quality of baseline performance, and under appropriate conditions manipulations of DA in the mPFC do not necessarily cause disruption of cognitive performance but can even improve poor performance. The D1 receptor also seems to be involved in the disrupting effects on cognitive performance of enhanced DA transmission. Thus, intra-mPFC infusion of the D1 agonist SKF81297 produced deficits in a delayed alternation task, an effect that could be antagonized by co-treatment with the D1 antagonist SCH23390 (Zahrt et al., 1997), although some evidence also exists that D2 receptors may be involved in the delayed alternation response impairment produced by ketamine (Verma and Moghaddam, 1996). Another elegant demonstra-
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tion of the relationship between dopaminergic tone and cognitive performance comes from another line of research. Acute exposure to stress can produce working memory deficits that can be ameliorated by treatments that reduce dopaminergic transmission (Murphy et al., 1996a,b; Arnsten and Goldman-Rakic, 1998). Given the high responsivity of the mesocortical DA neurons to stress (see section 2.2.2) this cognitive impairment during acute stress situations may be due to a hyperdopaminergic state in the PFC. On the other hand, Mizoguchi et al. (2000) showed that chronic stress also produces deficits in spatial working memory that is accompanied not by a hyperdopaminergic but rather by a hypodopaminergic prefrontal state. Interestingly in the present context, in the same study it was shown that intra-mPFC infusion of a D1 receptor agonist was able to reverse the working memory deficit. Furthermore, the hypodopaminergic prefrontal state in chronically stressed animals appeared to be largely due to reduced releasability of DA from presynaptic terminals in the mPFC since in these animals, unlike in control animals, it was not possible to stimulate DA release by infusion of KCl. Taken together, these results strongly suggest that hyper- as well as hypodopaminergic states in the mPFC (e.g. induced by acute or chronic stress, respectively) can produce working memory deficits that can be ameliorated by treatments that bring back the level of dopaminergic transmission to a ‘normal’ level, i.e. DA antagonists or DA agonists, respectively. These findings are in line with the notion of a predominant, although not exclusive, role of the D1 for mediating the effects of mPFC DA on cognition (Sawaguchi et al., 1990a,b; De Brabander et al., 1991; Sawaguchi and Goldman-Rakic, 1991, 1994; Arnsten et al., 1994; Smiley et al., 1994; Seamans et al., 1995b; Williams and Goldman-Rakic, 1995; Granon et al., 2000). The mechanism by which this ‘fine-tuned’ DA effect for optimum cognitive performance is achieved is not known but may be due to a ‘gating’ effect of DA in its interaction with other transmitters (in particular glutamate) in generating activity in prefrontal cortical pyramidal cells (Thierry et al., 1986; Smiley et al., 1994; Yang and Seamans, 1996; Yang et al., 1996a,b; Pirot et al., 1996; Bubser et al., 1997; Gulledge and Jaffe, 1998). According to this hypothesis, a too high tone of DA would ‘shut the gate’ for excitatory inputs onto pyramidal cells, and a too low tone of DA would facilitate ‘interferences’ between different inputs, both mechanisms leading to disruptions in cognitive performance. This view is indirectly supported by the finding that excitatory mediodorsal input and inhibitory input from the VTA converge on mPFC pyramidal cells and that the MD stimulation-evoked excitation in these cells can be blocked by simultaneous stimulation of the VTA (and also of the raphe nucleus, but of not of the locus
coeruleus, indicating that in this respect serotonin, but not noradrenaline, has similar effects as DA) (Ferron et al., 1984; Mantz et al., 1988, 1990; Thierry et al., 1990; Pirot et al., 1996). Furthermore, Bubser et al. (1997) showed that 6-OHDA lesions of the VTA increased intensity of Fos expression in the mPFC induced by pharmacological disinhibition of the mediodorsal thalamus, suggesting modulatory inhibitory effects of DA in the mPFC on glutamatergic transmission. Thus, information flow in the basal ganglia–thalamocortical circuit is under strong dopaminergic (and serotonergic, and, with respect to basal firing activity, also noradrenergic) control at the level of the mPFC. Furthermore, the dopaminergic mesocortical projection also exerts a potent modulatory influence on hippocampal input to the mPFC. Thus, DA not only inhibits spontaneous activity of mPFC neurons but also the excitation normally induced in these cells by stimulation of the hippocampus (Jay et al., 1995). In the same study it was also demonstrated that a population of mPFC neurons responding to hippocampal stimulation projects to the NAS and/or to the VTA, suggesting that the hippocampus can influence these subcortical areas via the mPFC and that DA can modulate this influence at the level of the mPFC. The role of the glutamatergic system for spatial working memory was also demonstrated by Romanides et al. (1999) who showed that not only an increased tone of prefrontal DA disrupted performance in a spatial delayed alternation task but also a decrease in glutamatergic tone that was achieved by intra-mPFC injections of the AMPA receptor antagonist CNQX or the NMDA receptor antagonist CPP, or by inhibition of glutamatergic afferents by injection of the GABA-B receptor agonist baclofen into the mediodorsal thalamus. As recently shown by Gurden et al. (1999), concurrent stimulation of the VTA at parameters known to produce DA release in the mPFC significantly enhances long-term potentiation (LTP) induced by stimulation of the hippocampo-prefrontal pathway. Conversely, electrolytic lesion of the VTA greatly reduced hippocampoprefrontal LTP. Given the important role of the hippocampus in learning and memory, it is obvious that this effect of mPFC DA on hippocampus-driven LTP may be an important element of its well documented role in memory function and cognitive processes. Yet, in the same series of experiments, Gurden et al. (1999) also found that, in contrast to the effects on LTP, VTA stimulation decreased the amplitude of postsynaptic responses of mPFC cells to hippocampal stimulation. Thus, DA not only has an important permissive influence on LTP in the mPFC, it also ‘gates’ hippocampal input to the mPFC independently of LTP mechanisms. A rather similar convergence of dopaminergic and glutamatergic inputs onto postsynaptic cells has also
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been demonstrated at the level of the NAS and striatum. Here, the dopaminergic axon terminals make contact with the necks of dendritic spines of spiny neurons and could therefore modulate the input from glutamatergic axon terminals which contact the heads of the same spines (i.e. the same ‘triad’ arrangement exists that has also been found in the mPFC for pyramidal cells, and dopaminergic and glutamatergic axon terminals) (Yang and Mogenson, 1984; Sesack and Pickel, 1990; Henriksen and Giacchiono, 1993; Mogenson et al., 1993; O’Donnell and Grace, 1994; Flores-Hernandez et al., 1997; Ce´peda et al., 1998; Ce´peda and Levine, 1998). In addition, terminals of mPFC efferents to the NAS/striatum not only converge onto spiny neurons with dopaminergic terminals but also with glutamatergic terminals of projections originating from amygdala, midline and intralaminar thalamic nuclei, entorhinal cortex and hippocampal complex (Kocsis et al., 1977; Pennartz and Kitai, 1991; O’Donnell and Grace, 1995; Finch, 1996). In fact, the degree of convergence is considerable, such that vitually none of the spiny neurons is innervated by only one of the different excitatory inputs. In particular, it has been shown that hippocampal input to NAS neurons can gate mPFC input to the same neurons (O’Donnell and Grace, 1995), and a gating of prefrontal cortical afferents of the NAS by afferents from the amygdala converging onto the same spiny neuron has also been described (Moore and Grace, 1996). From their findings, Grace and colleagues concluded that the hippocampus may provide a more ‘general-context dependent’ form of gating of information flow from the mPFC to the NAS, while the amygdala may provide a more discrete, ‘event-related’ form of gating of this information flow. This means that at the striatal level, information flow from the mPFC is not only modulated by converging dopaminergic input from the midbrain but also by converging glutamatergic input from the hippocampus, amygdala, and potentially other forebrain areas. These different glutamatergic inputs differ in the way they modulate each other, adding additional complexity and considerable computational power to the information processing at the level of the NAS. As mentioned above, the disruptive effects of NMDA receptor antagonists in mPFC-dependent cognitive tasks in rats and humans at low doses (Ghoneim et al., 1985; Morris et al., 1986; Parada-Turska and Turski, 1990; Wesierska et al., 1990; Krystal et al., 1994; Verma and Moghaddam, 1996) and the induction of psychotic symptoms in humans at higher doses has led to the idea that the functional deficits of schizophrenia might be even better modelled by the administration of NMDA receptor antagonists (such as PCP or ketamine) rather than by the administration of a DA agonist (Javitt and Zukin, 1991; Sams-Dodd, 1996, 1998a,b, 1999; Krystal et al., 1999; Lahti et al., 1999).
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The potent DA-releasing effects in the mPFC of highaffinity NMDA receptor channel blockers such as PCP or MK-801 may be central to their psychotomimetic and cognitive disrupting effects since memantine, a channel blocker with moderate affinity and high voltage dependency, that only weakly affects mPFC DA transmission (Bubser et al., 1992; Hesselink et al., 1999), has only weak psychotomimetic and cognitive disrupting effects in humans and in animal models of psychosis (Ditzler, 1991; Kornhuber et al., 1994; Danysz et al., 1997; Parsons et al., 1999). In fact, memantine is even used as a cognitive enhancer in dementia (Ditzler, 1991) and has been shown to improve learning in rats bearing entorhinal cortex lesions (Zajaczkowski et al., 1996). Thus, while the cognitive-behavioral effects of high affinity NMDA receptor antagonists appear to be dominated by their adverse effects which may be largely due to the mPFC DA release that these drugs produce, the beneficial cognitive-behavioral effects of channel blockers with low or moderate affinity are not masked or disrupted by the adverse effects brought about by DA release in the mPFC.
4. Functional heterogeneity of the mPFC as a possible cause for inconsistent data? It has been mentioned repeatedly throughout this review that manipulations of the mPFC have often yielded inconsistent results with respect to their behavioral and neurochemical effects. While different lesion techniques (e.g. ablation, excitotoxic, 6-OHDA, electrocoagulation), different neurochemical and physiological methods (e.g. ex vivo tissue analysis, in vivo microdialysis and voltammetry in anesthetized or freely moving animals, in vitro electrophysiology, in vivo electrophysiology in anesthetized or freely moving animals, different behavioral procedures and measures) may well account for many of the inconsistencies, another aspect that deserves further consideration is the anatomical and functional heterogeneity of the mPFC. Especially in the early studies (e.g. Richter and Hawkes, 1939; Zubek and De Lorenzo, 1952; Adler, 1961; Lynch et al., 1969, 1971; Glick, 1970, 1972; Lynch, 1970; Iversen, 1971; Iversen et al., 1971; Hannon and Bader, 1974; Kolb, 1974a,b), the various types of lesions (6-OHDA, electrolytic, excitotoxic, aspiration) often affected quite large but also variable regions of the frontal cortex and these often considerable variations in lesion location and lesion size (for 6-OHDA lesions this also includes the degree of DA depletion) must be kept in mind when discussing the apparently inconsistent results of these studies. In order to develop a more refined picture of the function of the mPFC (as well as other frontal cortical areas) it is without doubt necessary to employ more specific lesions, with respect to the size and local-
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ization of the lesion, and with respect to the neurotoxin employed in order to target specific types of cells while leaving other types of cells in the same area unaffected. The fact that the mPFC subareas (infralimbic, prelimbic, anterior cingulate, from ventral to dorsal) (van Eden and Uylings, 1985; Groenewegen et al., 1990; Uylings et al., 1990; van Eden et al., 1992) each have distinct afferent and efferent connections suggests that they are also functionally distinct. In brief, the infralimbic mPFC receives afferents from the hypothalamus, the VTA, amygdala, hippocampus and autonomic brain stem areas, but not from the MD (which is the reason why it is not considered as part of the mPFC by some authors). It sends projections preferentially to the NAS shell and the rostral MD, and also to the hypothalamus, amygdala and a number of autonomic brain stem nuclei. The prelimbic mPFC receives input from the rostral MD, the hippocampus, and the densest DA input from the VTA of all mPFC subdivisions. It projects preferentially to the NAS core and the rostral MD, and also to the VTA, basolateral amygdala, and other forebrain structures. The anterior cingulate mPFC receives afferents from the caudal MD, a number of neocortical areas, and also (to a small extent) the VTA, and projects preferentially to the dorsal striatum and the caudal MD, and to other neocortical and brainstem areas (Thierry et al., 1976b; Lindvall et al., 1978; Phillipson, 1979; Phillipson and Griffiths, 1985; Terreberry and Neafsey, 1987; Jay et al., 1989; Sesack et al., 1989; Conde´ et al., 1990, 1995; Groenewegen et al., 1990; Hurley et al., 1991; Berendse et al., 1992; Laubach and Woodward, 1995; Azuma and Chiba, 1996; Groenewegen et al., 1999). Assuming that this anatomical specificity and heterogeneity of the different mPFC subareas is also reflected in a functional differentiation and specificity of these subareas, it may well be that at least some of the inconsistencies in the literature concerning the function of the mPFC are due to experimental procedures which affected different mPFC subareas to a differential degree. Indeed, it is increasingly appreciated that the mPFC is not one single homogeneous entity but is comprised of several anatomically distinct subareas, and manipulations specifically restricted to individual subregions have shown that with a number of behavioral paradigms distinct functions of these subregions can be revealed (Kolb, 1974a; Sesack et al., 1989; Brito and Brito, 1990; Burns et al., 1993, 1996; Morgan et al., 1993; Granon et al., 1994; Mogensen and Holm, 1994; Granon and Poucet, 1995; Morgan and LeDoux, 1995; Seamans et al., 1995a; Delatour and Gisquet-Verrier, 1996; Kesner et al., 1996; Muir et al., 1996; Bussey et al., 1997a,b; Jinks and McGregor, 1997; Joel et al., 1997; Ragozzino et al., 1998; Tzschentke and Schmidt, 1998a,b,c, 1999, 2000a,b). However, from the publica-
tion years of these studies it is obvious that, with a few exceptions, the anatomical and functional heterogeneity has only very recently been widely appreciated and considered in the design of studies examining the function of the mPFC. This potentially high specificity of lesions effects is exemplified by our own studies which examined the effects of discrete subarea-specific excitotoxic quinolinic acid lesions on drug-induced reward as measured in the CPP paradigm, and behavioral sensitization. In these experiments it was found that morphine-induced CPP was blocked only by lesions of the whole mPFC or of the infralimbic subarea but not by lesions of the other subareas, while cocaine-induced CPP was blocked only by lesions of the whole mPFC or of the prelimbic subarea, but not by lesions of the other subareas. Remarkably, amphetamine-induced CPP was not affected by any of the lesions. Similar findings for cocaine and amphetamine were obtained in sensitization experiments, in that the development of cocaine-induced behavioral sensitization was blocked by lesions of the whole mPFC or of the prelimbic subarea but not by lesions of the other subareas. Also, the development of amphetamine-induced behavioral sensitization was not affected by any of the lesions. Furthermore, of the subarea-specific lesions, only lesions of the whole mPFC or the infralimbic subarea affected (i.e. reduced) spontaneous activity in a novel environment (Tzschentke and Schmidt 1998a,b,c, 1999, 2000a). A similar specificity of particular subareas within the mPFC in the context of sensitization was also found by other authors. Pierce et al. (1998) reported that only lesions of the dorsal, but not of the ventral aspects of the mPFC disrupt the expression of cocaine-induced sensitization. How can this apparent functional heterogeneity of the mPFC be explained? As mentioned above, there exists a topographical projection from the mPFC to the striatal complex. While the anterior cingulate mPFC projects preferentially to the dorsal striatum and the prelimbic mPFC projects preferentially to the NAS core, the infralimbic mPFC projects preferentially to the NAS shell (Berendse et al., 1992). For our observation that the infralimbic mPFC appears to be particularly important for the mediation of the rewarding effects of morphine it may be of relevance that the NAS shell expresses a higher density of mRNA for the m-opiate receptor than the NAS core or the dorsal striatum (Delfs et al., 1994; Mansour et al., 1995a,b) and in turn projects, via the ventral pallidum, to the PPTg (Heimer et al., 1991; Zahm and Heimer, 1993), a region also rich in m-receptors (Ding et al., 1996), that has been shown to be involved in opiate reward (Bechara and van der Kooy, 1989; Bechara et al., 1992). In addition, the infralimbic mPFC itself projects to and receives input from structures expressing rela-
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tively high densities of m-receptors, such as hippocampus, amygdala and autonomic brain stem nuclei (Hurley et al., 1991; Azuma and Chiba, 1996; Ding et al., 1996). Taken together, this evidence suggests that the infralimbic mPFC may be part of a circuitry that is particularly important for the mediation of morphine effects. Even if morphine does not initiate reward within the infralimbic mPFC, a possibility which is suggested by the fact that the mPFC contains only relatively low levels of m- and d-opioid receptors and preproenkephalin mRNA (Harlan et al., 1987; Bausch et al., 1995; Ding et al., 1996) and that the electrophysiological effects of morphine on mPFC neurons are mediated predominantly in afferent structures (Giacchiono and Henriksen, 1996), destruction of this site may disrupt the circuitry necessary for the development of morphine-induced CPP. In our own studies, cocaine-induced CPP was only disrupted by prelimbic and whole mPFC lesions, but not by infralimbic and anterior cingulate mPFC lesions. The observation that a lesion of the mPFC can disrupt the rewarding effects of cocaine is in line with a previous report (Isaac et al., 1989). We are unaware of any mapping study exploring the boundaries of cocaine self-injection sites within the mPFC, but the sites used in previous studies seem to have largely targeted the prelimbic subarea (Goeders and Smith, 1983, 1986, 1993; Goeders et al., 1986). The seemingly particular importance of the prelimbic mPFC may also be related to the fact that this part of the mPFC (along with the infralimbic mPFC) receives the densest dopaminergic innervation of all frontal cortical areas (Emson and Koob, 1978; Lindvall et al., 1978). In the same context it may also be of relevance that the prelimbic mPFC has a stronger projection to the VTA than the other mPFC subareas (Beckstead, 1979; Sesack et al., 1989; Hurley et al., 1991). To make things even more complicated, there is evidence that even within these different subregions functionally distinct subfields exist (Takenouchi et al., 1999), making it even more obvious that the localization of particular functions within the prefrontal cortex is highly specific and can only be accessed and assessed with anatomically equally specific methods.
5. Concluding remarks In summary, although the existing data is too heterogenous to draw a detailed general picture of the functional role of the mesocorticolimbic system, one general picture that emerges is that DA in the mPFC does not have an ‘executive’ function in the sense that dopaminergic signals in the mPFC become directly manifest as a concrete behavioral output or physiological response. Rather, the role of prefrontal cortical DA
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appears to be modulatory. This statement is primarily based on the common (but by no means consistent) finding that DA depletion of the mPFC does not cause any overt behavioral deficits and only few overt neurochemical alterations, as long as tests are conducted under ‘baseline’ conditions, i.e. in the absence of a behavioral of pharmacological challenge. If, however, an organism is challenged in a state of reduced mPFC DA transmission (induced either by 6-OHDA lesions or local injections of DA receptor antagonists) it becomes obvious that the mesocortical system usually acts in an inhibitory fashion on subcortical DA activity. This is then manifest in an increased behavioral and neurochemical response to an appropriate environmental or pharmacological challenge. The inhibitory influence of prefrontal cortical DA over various subcortical structures, including the NAS, has already been discussed extensively (Carlsson and Carlsson, 1990; Le Moal and Simon, 1991). Another point which deserves further consideration is the following: How is it possible that DA in the NAS has locomotor-inducing and rewarding effects while DA in the mPFC has also rewarding effects but has inhibitory effects on locomotion? This appears to be some kind of paradox, in particular when considered in light of the postulate that reward and locomotion are homologous manifestations of the same central brain mechanism (Wise and Bozarth, 1987). The first point that has to be addressed here is whether DA in the mPFC does really provide an essential reward signal. The only strong evidence for this comes from the series of studies by Goeders, Smith and collegues (Goeders and Smith, 1983, 1986; Goeders et al., 1986) demonstrating that cocaine and DA itself is self-administered into the mPFC, and that this cocaine self-administration is dependent on the dopaminergic innervation of the mPFC. All other evidence pointing to a role of prefrontal DA in reward is either not very strong or alternative interpretations are available to account for the findings. Furthermore, a number of findings argue against a crucial role of prefrontal DA in reward (see section 3.1). In several cases where an involvement of the mPFC in rewarding mechanisms has been demonstrated, the effects can in large part be explained without invoking prefrontal DA. Thus, the rewarding effects of self-administered NMDA-receptor antagonists in the mPFC demonstrated by Carlezon and Wise (1996a) are likely to be independent of DA and may be due to a disinhibition of pyramidal cells projecting to the VTA (via inhibition of mPFC GABAergic interneurons), or alternatively, to an inhibition of pyramidal cells projecting to the NAS. Both alternatives would lead to decreased activity in NAS spiny neurons, which is considered by some authors to be a common denominator of different reward signals converging onto the NAS (Wise, 1996a). Remarkably, as mentioned previ-
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ously, Goeders and Smith themselves have argued that cocaine in the mPFC produces effects resembling those observed after 6-OHDA lesions of the mPFC (Goeders and Smith, 1993). Clearly, this paradox awaits further examination and clarification. Based on the results of a series of studies, Di Chiara and collegues have suggested that the reinforcing efficacy of drugs of abuse is related to their ability to cause an increase in extracellular DA in the NAS but is unrelated to their effects on DA or NA release in the mPFC (Di Chiara et al., 1993; Di Chiara, 1995; Bassareo et al., 1996; Pontieri et al., 1996; Tanda et al., 1994, 1996, 1997). This suggestion was based on the observation that all drugs of abuse that were examined clearly showed stronger effects on NAS DA than on mPFC DA and that drugs that showed a preferential or exclusive effect on mPFC DA and/or NA (such as the selective NA reuptake blockers oxaprotiline and DMI) clearly do not have abuse potential. Taken together, although evidence that DA in the mPFC reduces locomotor activity (i.e. acts ‘antagonistically’ to subcortical DA) is very good, evidence that DA in mPFC directly mediates rewarding effects is weak, and the available data rather suggest that reward elicited within the mPFC (by drugs or stimulation) may be largely independent of DA within the mPFC. Thus, although the mPFC as such undoubtedly plays a rather important role in the brain reward system, the crucial reward-relevant elements in the mPFC are probably not the dopaminergic inputs but rather the pyramidal cells with their glutamatergic projections to the midbrain and possibly to the NAS. While DA in the mPFC may be sufficient to produce rewarding effects (at least in the case of cocaine), it is does not appear to be a necessary reward signal.
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