Chapter 18 Influence of the ascending monoaminergic systems on the activity of the rat prefrontal cortex

H.B.M. UYlings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner and M.G.P. Feenstra (Eds.) Progress in Brain Research., Vol R5 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)

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CHAPTER 18

Influence of the ascending monoaminergic systems on the activity of the rat prefrontal cortex A.-M. Thierry, R. Godbout, J. Mantz and J. Glowinski Inserm

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114, Coll&e de France, Chaire de Neuropharmacologie, 75231 Paris Cedex 05, France

Introduction The influence of the brain stem on the activity of the cerebral cortex was originally demonstrated by Moruzzi and Magoun (1949) who described the “ascending reticular activating system”. This influence was believed to be exclusively indirect until noradrenergic (NA) and serotoninergic (5HT) neurons in the brainstem, NA and 5HT fibers in the cerebral cortex were visualized (Dahlstrom and Fuxe, 1964). Then, the use of new anterograde and retrograde tracing techniques and the improvements in histochemical fluorescence methods allowed to demonstrate the existence of direct reticulo-cortical NA and 5HT projections (Lindvall and Bjorklund, 1984; Fallon and Loughlin, 1987). It was also shown that dopaminergic (DA) terminals are present in the cerebral cortex (Thierry et al., 1973) and that the cortical DA innervation originates from the brainstemmesencephalon (Lindvall and Bjorklund, 1984). The rat medial prefrontal cortex (PFC) is one of the cortical regions innervated by the 3 aminergic systems, i.e., DA, NA, and 5HT (Fig. 1). The DA innervation of the PFC, which is particularly dense in deep layers (V and VI), mainly originates from Correspondence:Dr. A.-M . Thierry, INSERM U. 114, College de France, Chaire de Neuropharmacologie, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France.

the A10 group of DA cells located in the ventral tegmental area (VTA) and its adjacent regions (Lindvall and Bjorklund, 1984). Whereas DA neurons of the VTA also innervate limbic subcortical regions, distinct cells project specifically either to cortical or to subcortical structures (Thierry et al., 1984). In contrast to the restricted distribution of DA terminals in specific cortical areas, the NA and 5HT fibers distribute throughout the whole cerebral cortex (Fallon and Loughlin, 1987). Ascending NA fibers, which originate from the locus coeruleus (LC), collateralize extensively and innervate the anteroposterior axis of the cerebral cortex as well as subcortical structures. In the PFC, as in most other cortical areas, NA terminals are distributed in all cortical layers with a predilection for molecular layer I. The 5HT projections to the cerebral cortex arise from the dorsal (DRN) and median (MRN) raphe nuclei of the mesencephalon. Similarly to the LC neurons, individual cells of the DRN or MRN may project not only to cortical but also to subcortical structures. The 5HT innervation of the cerebral cortex is more dense than the NA innervation; 5HT fibers are distributed in all cortical layers and their density in the PFC is significantly greater in layer I (Audet et al., 1989). Analysis of the influence of the aminergic ascending systems on cerebral functions has generated considerable interest since several psychoactive

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Fig. 1 . Schematic representation, on coronal sections, of the monoaminergic pathways from the locus coeruleus (LC), dorsal and median raphe nuclei (DR, MR), and ventral tegmental area (VTA) to the prefrontal cortex (PFC). Me5, mesencephalic trigeminal nucleus; SN, substantia nigra; Acb, accumbens nucleus.

drugs (such as antidepressants, neuroleptics, amphetamine, etc.) are known to interfere with DA, NA or 5HT neurotransmission. However, the role of monoamines in the PFC has not yet been studied extensively. The PFC has a determining influence in the regulation of emotional states, in the control of motor activity and in cognitive processes such as representational memory (Kolb, 1984; Goldman-Rakic, 1987; Fuster, 1989). Experimental evidence suggests that DA and NA neuronal systems exert a major control in these functions. First, the particularly high reactivity of the mesocortical DA system to stressful situations (as compared to the mesolimbic and the nigrostriatal DA systems) has been underlined by various authors (Thierry et al., 1984). Second, lesion of the mesocortical DA system has been shown to induce an increase in locomotor activity in the rat; this effect is observed only if the NA innervation is preserved, suggesting that important interactions

between DA and NA systems take place at the cortical level (Taghzouti et al., 1988). Third, the specific loss of DA in the PFC of rats or monkeys was associated with severe impairments in a cognitive test, the delayed alternation task (Brozoski et al., 1979; Simon et al., 1980). Moreover, it has been recently reported that the administration of an a2-adrenergic agonist improved spatial delayed-response performance in aged rhesus monkeys (Arnsten and GoldmanRakic, 1985). Finally, no direct study has analyzed the influence of 5HT in PFC functions. However, it is known that the 5HT ascending system may interfere with the mesocortical DA system, since the lesion of MRN induced a decrease of DA turnover in the PFC (Herd et al., 1981). It thus appeared of importance to analyze the respective roles of the ascending aminergic systems in the control of the activity of PFC neurons. We will review recent electrophysiological studies performed in the rat in

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which we have compared the modulatory influence of the DA, 5HT and NA ascending systems on the spontaneous or evoked activity of PFC cells.

(I) Electrophysiological characteristics of DA, 5HT and NA neurotransmission in the PFC The electrophysiological effects of iontophoretic application of DA, NA or 5HT on the activity of cortical cells are still controversial. However, inhibition of the spontaneous firing is the most common effect reported in the cerebral cortex (Foote et al., 1983; Phillis, 1984). For comparison, it was thus of interest to analyze the influence of the stimulation of the DA, 5HT and NA ascending systems on the spontaneous activity of PFC neurons in anesthetized rats.

(A) Influence of the DA system The electrical stimulation of the VTA (at a frequency of 1 Hz) induced an inhibitory response in the majority (80%) of PFC cells recorded in layers 111-VI. The mean duration and latency of these responses were 110 msec and 18 msec respectively (Fig. 2). Some of the inhibited cells could be identified as output PFC neurons by antidromic activation (Ferron et al., 1984; Peterson et al., 1987). Whether the inhibition is exerted directly or via intracortical interneurons in contact with efferent PFC cells, as suggested in a recent in vitro study, is not yet established (Penit-Soria et al., 1987). Several data indicate that the responses induced by VTA stimulation are mediated by the activation of the mesocortical DA neurons (Ferron et al., 1984): (1) The latency of the inhibitory responses was compatible with the slow conduction velocity of mesocortical DA fibers. (2) The inhibitory responses were markedly reduced after pharmacological depletion of catecholamines with amethyl-paratyrosine (u-MPT) treatment or following destruction of the ascending catecholaminergic systems by local microinjection of 6-hydroxydopamine (6-OHDA). After specific lesions of the NA system which spared DA neurons, the inhibitory responses of PFC neurons induced by VTA stimu-

lation persisted and their duration was even slightly longer. (3) The iontophoretic application of DA inhibited the spontaneous activity of PFC cells (Bunney and Aghajanian, 1976). Biochemical studies have revealed the existence of 2 types of DA receptors in the central nervous system: the D,, which is positively coupled to adenylate cyclase, and the D2, which is negatively coupled or not linked to adenylate cyclase (Stoof and Kebabian, 1984). These 2 types of receptors are present in the PFC (Bockaert et al., 1977; Bouthenet et al., 1987). Experiments have been done in order to characterize the type of DA receptors involved in the DA induced electrophysiological responses in the PFC. The systemic administration of neuroleptics such as

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Fig. 2. Effect of VTA and MRN stimulation on spontaneous and evoked activity of PFC cells. Peristimulus time histograms showing the inhibitory responses in 2 neurons of the PFC to single pulse stimulation (1 Hz) of the VTA (upper pannel) and MRN (lower pannel). Insets: Raster dot-displays showing the excitatory responses induced by MD stimulation ( 5 Hz)on these cells and the inhibition of the MD evoked responses by previous stimulation of the VTA (upper inset) and MRN (lower inset).

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sulpiride, spiroperidol, fluphenazine or cisflupentixol markedly decreased the inhibitory responses of PFC neurons to VTA stimulation (Thierry et al., 1986; Peterson et al., 1987). On the other hand, other neuroleptics, levomepromazine and the palmitic ester of pipothiazine did not antagonize, and even slightly increased, the duration of the VTA induced inhibition. The inhibition of the spontaneous activity of cells in deep layers of the PFC induced by the iontophoretic application of DA was specifically blocked by sulpiride, a selective D, antagonist, but not by SCH23390, a selective D, antagonist (Sesack and Bunney, 1989). These data are in favor of the involvement of D, receptors in the inhibitory effect of DA on PFC cells. However, some data suggest that the PFC D, receptor is not identical to the D, subtype described in subcortical structures. Indeed, the iontophoretic application of a specific D, agonist, LY171555, with or without the presence of a D, agonist, failed to inhibit the firing of PFC cells (Sesack and Bunney, 1989). Furthermore, the systemic administration of the neuroleptic haloperidol blocked the inhibitory responses induced by VTA stimulation in the nucleus accumbens but not in the PFC (Thierry et al., 1986). (B) Influence of the 5HT systems

Electrical stimulation of DRN and MRN has been shown to inhibit the spontaneous activity of cingulate, frontoparietal and sensorimotor cortical neurons (Olpe, 1981; Jones, 1982). Recently, we have found that PFC neurons mainly recorded in layers 111-VI were also inhibited, and that a greater proportion of these neurons were affected by MRN (53%) than by DRN (35%) stimulation (Mantz et al., 1990). The mean durations and latencies of the inhibitory responses were 82 msec and 18 msec respectively after MRN stimulation and 75 msec and 18 msec after DRN stimulation (Fig. 2). The greater potency of MRN stimulation could be due to a preferential activation of MRN than DRN fibers when stimulated at a frequency of 1 Hz, since 2 distinct types of 5HT fibers arising

from DRN and MRN respectively innervate the cerebral cortex (Kosofsky et al., 1987). A coactivation of efferent DRN fibers could also occur when the MRN is stimulated. Indeed, all neurons inhibited by DRN stimulation were also inhibited by MRN stimulation, but the reverse was not systematically observed. A convergence of the effect of MRN and VTA stimulation on a same PFC cell was often found. However, the effect of MRN stimulation appeared to be less potent, the duration of the inhibitory responses was of shorter duration (82 msec and 110 msec after MRN and VTA stimulation respectively) and a smaller population of PFC neurons was effected by MRN (53%) than by VTA (80%) stimulation. The inhibition of the spontaneous firing of PFC neurons induced by raphe nuclei stimulation is very likely related to the activation of 5HT ascending systems. Indeed, microiontophoretic application of 5HT on PFC cells has been reported to decrease their firing rate (Lakovski and Aghajanian, 1985). The selective lesion of 5HT ascending fibers by local microinjection of 5,7-dihydroxytryptamine (5,7-DHT) markedly reduced the number of PFC neurons inhibited by DRN or MRN stimulation (Mantz et al., 1990). Using radioligand binding techniques 2 main subtypes of 5HT receptors (5HT, and 5HT2) have been described on the basis of their differential affinities for particular ligands (Peroutka, 1988). Both types of 5HT receptors are present in the PFC; however, of the different brain areas, the PFC is one of the structures which contains the highest density of 5HT, receptors (Pazos and Palacios, 1985; Pazos et al., 1985). Acute systemic administration of specific 5HT2 receptor antagonists such as ketanserin or ritanserin blocked the inhibitory responses of PFC cells induced by MRN stimulation suggesting that these responses could be mediated through 5HT2 receptors (Mantz et al., 1990). (C) Influence of NA ascending system

In contrast to the effects observed following elec-

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trical stimulation of the VTA and of the raphe nuclei, single-pulse stimulation (1 Hz) of LC did not induce reliable modifications in the spontaneous activity of PFC cells (Mantz et al., 1988). However, when a higher frequency of stimulation was used, a marked decrease in the firing rate of PFC neurons was observed. Trains of pulses at a frequency of 20 Hz applied for 10 sec in the LC produced a long-lasting post-stimulus inhibition (mean duration = 45 sec) of the spontaneous discharge in 57% of the PFC cells tested (Fig. 3). This effect was decreased markedly following depletion of cortical catecholamines by a-MPT pretreatment or selective destruction of the NA ascending pathways by local 6-OHDA injections, suggesting that these inhibitory responses are mediated by NA neurons (Mantz et al., 1988). Moreover, microiontophoretic application of NA has been shown to decrease the spontaneous activity of PFC cells (Bunney and Aghajanian, 1976). Inhibitory responses induced by local application of NA or stimulation of the LC in different cortical areas were shown to be antagonized by /3adrenergic blocking agents (Olpe et al., 1981). However, various types of electrophysiological

responses to NA have been reported in the cortex (Foote et al., 1983). The respective contribution to these effects of the different adrenoreceptor subtypes linked to distinct transductional mechanisms has not yet been clearly delineated. Some PFC neurons are sensitive to both NA and DA, but cells in layers I1 and I11 are more sensitive to NA than DA, whereas in layers V and VI the reverse is found (Bunney and Aghajanian, 1976). In agreement with this observation and with the fact that, in our study, some PFC neurons showed typical inhibitory responses to both LC and VTA stimulations, it can be concluded that there is a convergence of the effects of NA and DA ascending systems on PFC cells. (11) Respective roles of the ascending DA, 5HT and NA ascending systems in the control of evoked responses in the PFC

Several authors have analyzed the effect of iontophoretic applications of DA, 5HT or NA on evoked responses in cortical cells (Foote et al., 1983; Phillis, 1984). DA or 5HT have been shown to reduce the excitatory responses induced by the

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Fig. 3. Effect of LC stimulation on the spontaneous and evoked activity of a PFC cell. (Left panel) Time - frequency histogram showing the long lasting post-stimulus inhibition induced by LC stimulation (20 Hz, 10 sec) on the spontaneous activity of a PFC neuron. The period of stimulation is indicated by the horizontal bar and the concomitant peak corresponds to the stimulus artefact. (Right panel) Raster dot-displays showing the excitatory responses induced by MD stimulation ( 5 Hz)applied before (arrow A) or after (arrow B) LC stimulation. Note that when MD stimulation is applied during the post-stimulus inhibitory period induced by LC stimulation, the MD evoked responses are preserved.

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iontophoretic application of glutamate or acetylcholine. In contrast, NA decreased the basal firing of the cells but did not block the effect of acetylcholine. In addition, the iontophoretic application of NA reduced the spontaneous firing to a greater extent than the increased activity evoked by acoustic stimulation in the auditory cortex of the awake monkey (Foote et al., 1975). More recently, a facilitating effect of NA on somatosensory responses was described in primary sensory areas of the rat neocortex (Waterhouse and Woodward, 1980). In this model, 5HT typically exerted a different effect, i.e. the iontophoretic application of 5HT on somatosensory cortical neurons preferentially suppressed the excitatory responses to tactile stimuli (Waterhouse et al., 1986). In order to further understand the impact of DA, 5HT and NA neurons on their target cells in the PFC we have analyzed their influence on 2 types of evoked responses in the PFC of ketamine anesthetized rats: (1) the excitatory responses induced by electrical stimulation of the mediodorsal nucleus of the thalamus (MD), the main thalamic afferent to the PFC, and (2) the excitation produced by a noxious peripheral stimulus (intense tail pinch). (A) Influence of the monoaminergic systems on MD evoked responses

The electrical stimulation of the MD at a frequency of 5 - 10 HZ elicited a single response (mean latency; 16 msec) in 80% of PFC cells. These excitatory responses very likely originate from the activation of MD neurons since they were markedly reduced after local microinjection of kainic acid in the MD (Ferron et al., 1984). A convergence on the same PFC cell of the effects of MD stimulation and of the activation of DA, 5HT and NA ascending systems was observed. Most of the cortical cells inhibited by VTA or MRN stimulation could be excited by the stimulation of the MD. When VTA or MRN stimulation were triggered respectively 3 - 45 msec or 5 - 35 msec prior to MD stimula-

tion, the excitatory responses were blocked (Fig. 2) (Ferron et al., 1984; Mantz et al., 1990). In contrast to what was observed with the DA and 5HT systems, the activation of the NA ascending system did not affect the MD-evoked responses (Fig. 2). The excitatory responses induced by MD stimulation applied at different time intervals after LC stimulation (performed at 20 Hz for 10 sec) were always preserved even though the spontaneous firing of PFC cells was markedly decreased (Mantz et al., 1988).

(B) Influence of monoaminergic systems on noxious tail pinch evoked responses The application of an intense tail pinch (applied for 10 sec) led to an activation of 25% of PFC cells. The usual pattern of the response was an increase in the firing rate occurring 1 - 5 sec after the onset of the pinch which lasted throughout the pinch application and in some cases for a longer period (2 - 20 sec). Units activated by noxious tail pinch also responded to noxious thermic stimulation (immersion of the tail in hot water). On the other hand, the activity of these cells was not affected by hair movements, light touch, slight persistent pressure or passive joint movements (Mantz et al., 1988). VTA stimulation (10 Hz) inhibited completely the spontaneous activity of most of the PFC cells sensitive to tail pinch. When tail pinch was applied during VTA stimulation the excitatory response to the painful stimulus was also completely blocked (Mantz et al., 1988). Similarly, the increased firing evoked by tail pinch was markedly reduced when the stimulus was applied during MRN stimulation (10 Hz) (Mantz et al., 1990). In all cases, the evoked response to tail pinch reappeared after the VTA or MRN stimulation period. In contrast, when tail pinch was applied during the inhibitory period induced by LC stimulation (20 Hz during 10 sec) the excitatory response to the noxious stimulus was always preserved (Mantz et al., 1988).

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(111) Conclusion

Ascending DA, 5HT and NA neurons which originate respectively from the VTA, the raphe nuclei and the locus coeruleus modulate markedly neuronal activity in the PFC. The main differences in the influence of DA and 5HT compared to NA afferents on the spontaneous activity or evoked responses of PFC cells were underlined in this brief review. Indeed, activation of the DA or 5HT systems induces a phasic inhibition of the spontaneous firing rate of PFC neurons and blocks the excitatory responses elicited by thalamic stimulation or by a noxious peripheral stimulus. In contrast, the activation of the NA system elicits a long lasting inhibition of the basal firing of cortical cells without blocking the evoked responses, thus enhancing the signal-to-noise ratio. The influence of the 3 aminergic systems was observed on efferent PFC neurons. A characteristic of the output PFC neurons, in the rat, is the extensive collateralization of their axons (Ferino et al., 1987). By modulating the activity of these efferent PFC neurons, DA, 5HT and NA afferents indirectly control the activity of distinct subcortical structures such as the nucleus accumbens or the striatum. For example, it is known that DA denervation of the nucleus accumbens or the striatum leads to the development of D, receptor hypersensitivity in these structures. It has been shown that destruction of DA terminals in the PFC prevented this phenomenon ( H e r d et al., 1989). In conclusion, it appears that the DA, 5HT and NA ascending systems control neuronal activity in the PFC and modulate the transfer of information towards subcortical structures. By modifying the responsiveness of PFC neurons to afferent synaptic inputs, disregulation of the aminergic neurotransmissions may, therefore, induce disorders of motor activity, emotion or cognitive processes, functions in which the PFC plays a prominent role. References Arnsten, A.F.T. and Goldman-Rakic, P.S. (1985) Alpha-2adrenergic mechanisms in prefrontal cortex associated with

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J.Seheel-Kriiger: What is the possible contribution of locus coeruleus and MRN/DRN raphe innervation of VTA dopamine

365 cells in VTA on the response of dopamine inhibitory effect on PFC cells? A direct effect on PFC or indirect via VTA? A.M. Thierry: After lesioning of the VTA area, raphe stimulation and locus coeruleus still produce their distinct inhibitory effects in PFC, indicating the direct projection to PFC is very important. The technique of stimulation, however, may be too crude to provide detailed analyses of the delicate interactions between locus coeruleus or raphe and VTA cells. M.A. Corner: Is the differential effect of NA vs. 5HT stimulation specific for the PFC, or do other cortical regions respond in a similar fashion? A.M. Thierry: Results from other labs, mostly on visual and somatosensory cortex, indicate similar principles operating over the entire (neo) cortex. C.G. van Eden: Are the inhibitory effects of monoamines (especially NA which needs a prolonged stimulation) on PFC cells produced by monosynaptic contacts? A.M. Thierry: From our results it cannot be concluded that the effects are produced by monosynaptic contacts: the implication of cortical GABAergic interneurons is currently under investigation. Concerning the effect of LC stimulation, similar data have been obtained in other target structures of the LC, using this particular pattern of stimulation. This could be related to the characteristics of NA fibers: they show abundant collateralization, variability in the excitability of cell bodies and fibers, and inhibitory recurrent collaterals. E.F. Neafsey: What about conduction velocity from PFC to subcortical targets? A.M. Thierry:: The conduction velocity of efferent cortical fibers is very slow (0.5 - 1 m/sec), corresponding to a conduction time of 10-20 msec.

H.B.M. Uylings: Does the successive order of stimulation in the different brain regions (like VTA after MD or MD after VTA) influence the electric activity response in the PFC cells? A.M. Thierry: In order to block the excitatory response induced by MD stimulation VTA stimulation has to be applied 3 - 45 msec before that of MD. A.Y. Deutch: Do neurons contributing to corticofugal projections to different subcortical structures (e.g., mediodorsal thalamus, striatum) respond to different degrees of evoked inhibition? A.M. Thierry: Most corticofugal projections collateralize to multiple subcortical targets, so at the present time it is not possible to determine if differences exist - present data would suggest no differences. J.P.C. de Bruin: (1) How can 6-OHDA lesions of the VTA affect either mesocortical or mesolimbic DA systems in a specific way? (2) The recordings were all made in medial PFC. Can the data be generalized to orbital PFC? A.M. Thierry: (1) Pretreatment with DMI partially protects DA neurons which project to the PFC but not those which project to nucleus accumbens. (2) We have not made recordings in the lateral PFC, but I would suggest that similar results would have been obtained. C. Vidal: How d o you explain the inhibition seen after stimulation of MD at low frequency stimulation? A.M. Thierry: We do not have any explanation yet, because we need intracellular recordings for that. There may be two possibilities: one is a different sequence in EPSP - IPSP according to the frequency of stimulation; the other could be that different populations of cells are activated.