Review
TRENDS in Neurosciences
Vol.30 No.5
Dopamine: 50 years in perspective Susan D. Iversen and Leslie L. Iversen University of Oxford, Departments of Experimental Psychology and Pharmacology, Oxford OX1 3QT, UK
The discovery of dopamine as a neurotransmitter in brain by Arvid Carlsson approximately 50 years ago, and the subsequent insight provided by Paul Greengard into the cellular signalling mechanisms triggered by dopamine, gained these researchers the Nobel Prize for Medicine in 2000. Dopamine research has had a greater impact on the development of biological psychiatry and psychopharmacology than work on any other neurotransmitter. Neuropsychological views of the role of dopamine in the CNS have evolved from that of a simple reward signal to a more complex situation in which dopamine encodes the importance or ‘salience’ of events in the external world. Hypofunctional dopamine states underlie Parkinson’s disease and attention deficit hyperactivity disorder, and there is increasing evidence for dopamine hyperactivity in schizophrenia. Some of the medicines that are most widely used in psychiatry, such as L-DOPA, methylphenidate and neuroleptic drugs, act on dopaminergic mechanisms. Introduction The first 40 years of dopamine research culminated in the award of the Nobel Prize in Physiology and Medicine 2000 to Arvid Carlsson and Paul Greengard, two of the pioneers in this field. More than work on any other neurotransmitter, basic research on dopamine has greatly influenced our understanding of neuropsychiatric illnesses and contributed to the development of modern psychopharmacology. Any account of the historical perspective must inevitably be highly personal, and we recognize that the following perspective reflects our own biases in this respect. Discovery In his Nobel Lecture in 2000, Carlsson described how in Hillarp’s laboratory in Lund he discovered dopamine in the brains of reserpinized animals treated with L-DOPA, by using the then newly developed analytical tool of spectrophotofluorimetry (http://nobelprize.org/nobel_prizes/ medicine/laureates/2000/carlsson-lecture.html). Carlsson went on to show that dopamine was a normal brain constituent and mapped its regional distribution, highlighting the exceptionally high concentrations of dopamine in basal ganglia. His suggestion that dopamine might represent a neurotransmitter in brain met, however, with almost unanimous rejection at a CIBA Foundation Meeting held in London in 1960 [1]: the idea that synaptic transmission in the CNS was electrical rather than chemical was still firmly entrenched! Corresponding author: Iversen, L.L. (
[email protected]). Available online 26 March 2007. www.sciencedirect.com
Dopamine receptors and signalling Progress in the biochemical characterization of dopamine receptors in brain began with the discovery of a dopaminestimulated adenylyl cyclase first in the pituitary gland and then in brain [2]. This discovery offered for the first time a simple test-tube model for studying the actions of dopamine agonist and antagonist drugs, and initially seemed to provide support to the hypothesis that neuroleptic drugs acted through dopamine receptors in brain. But although the model fitted some classes of neuroleptics (phenothiazines and thioxanthenes), others (butyrophenones and substituted benzamides) were only weakly active [3]. It was not until another biochemical model involving binding of the radiolabelled butyrophenone spiperone to brain membranes was developed [4,5] that a better correlation between receptor affinities of neuroleptic drugs and clinical potencies became apparent – in a graph that has since become a classic in psychopharmacology. We now understand that the dopamine-stimulated adenylyl cyclase represents a model of the D1 dopamine receptor, whereas the binding of radiolabelled spiperone or other potent neuroleptics reflects the D2 dopamine receptor. Subsequent molecular pharmacology research revealed three other members of the dopamine receptor family: D3, D4 and D5 [6]. Although the availability of simple in vitro models for studying dopamine receptors has proved valuable to the pharmaceutical industry in screening for novel neuroleptic drugs, it has not led to a quantum leap in advancing the treatment of schizophrenia. An important advance in recent years has been the understanding that a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors provides drugs that retain anti-psychotic activity but have reduced Parkinsonian motor sideeffects – the so-called ‘atypical neuroleptics’ [7]. Another advance has been the introduction of aripiprazole, the first partial agonist acting at the D2 receptor, as a novel antipsychotic medicine [8]. Research by Greengard [9] and others greatly advanced our knowledge of the cell signalling mechanisms triggered by the activation of dopamine receptors. Their work has provided a model for other studies of ‘slow synaptic transmission’ and has led to the understanding that dopamine and other monoamines do not ‘mediate’ fast synaptic transmission in the CNS, but ‘modulate’ it. Greengard’s work showed that dopamine acting on D1 receptors activates the formation of cAMP, which in turn activates a cAMP-sensitive protein kinase that increases phosphorylation of a substrate known as DARPP-32 (an acronym for ‘dopamine and cAMP regulated phosphoprotein, molecular weight 32 kDa’) and simultaneously inhibits phosphatase
0166-2236/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2007.03.002
Review
TRENDS in Neurosciences
1. DARPP-32 has a key role in mediating the actions of dopamine, which in turn link to numerous other neurotransmitter mechanisms, ion channels and transcription factors [9]. So far, the complexity of these cellular signalling mechanisms is understood in greater detail for dopamine than for any other ‘slow acting’ neurotransmitter, and this pioneering research offers guidance for much future work. Dopamine release in vivo Several different experimental approaches have been used to measure the release of dopamine in the intact brain in vivo. The Glowinski group [10] developed methods for detecting the release of newly synthesized radiolabelled dopamine using stereotactically placed, push-pull cannulae through which a radiolabelled precursor ([3H]tyrosine) could be infused. This group was among the first to detect the dendritic release of dopamine in the substantia nigra and to study the presynaptic regulation of dopamine release in basal ganglia [10,11]. Others have developed miniature voltammetric electrodes for implantation [12]. The most widely used method has been intracerebral dialysis, where miniature probes are implanted from which minute quantities of dopamine and its metabolites can be separated by high pressure liquid chromatography and measured by electrochemical detection [13]. This method has been widely applied to many subsequent studies of dopamine release in vivo in response to drugs and other environmental stimuli. None of these methods can be used in human brain. In recent years, however, the advent of positron emission tomography (PET) imaging techniques and the development of a series of radiotracers that bind selectively to dopamine receptors or the dopamine transporter, or that are substrates for biosynthetic enzymes ([18F]L-DOPA), has provided completely new ways of assessing the functional state of the dopamine system in the human brain [14–16]. Dopamine pathways, neurophysiology and behaviour Anatomical studies have greatly aided our understanding of the contribution of dopaminergic pathways to behaviour. Application of the Falck–Hillarp fluorescence histochemical method by the ‘Swedish School’ and others defined in broad outline the three major trajectories of the midbrain dopamine neurons to (i) the dorsal striatum, (ii) the ventral striatum (including the nucleus accumbens), and (iii) the prefrontal cortex [17,18]. The use of 6-hydroxydopamine as a selective neurotoxin for catecholamine neurons was also a valuable advance [19]. Dopaminergic pathways to the dorsal striatrum A much-used behavioural model involved unilateral 6-hydroxydopamine lesions to the nigro-striatal pathway, resulting in ipsilateral or contralateral turning behaviour on administration of amphetamine or direct-acting dopamine agonists [20]. Subsequent research confirmed the importance of the nigro-striatal pathway in motor behaviour, both simple and complex, unconditioned and conditioned [21]. Anatomical and neurophysiological studies [22] continued to define how the interaction between the www.sciencedirect.com
Vol.30 No.5
189
patch or matrix organization of the dorsal striatum is pivotal in coordinating the multiple, parallel, recurrent anatomical loops linking the midbrain, basal ganglia, thalamus and cortex that underpin motor behaviour [23,24]. The finding in the rat that foetal dopamine neurons survive transplantation from the ventral midbrain to the 6hydroxydopamine-lesioned dorsal striatum and restore impaired motor functions [25] led to the experimental use of dopamine grafts in individuals with Parkinson’s disease [26]. Further grafting studies in rats confirmed the topographical cortico-striatal organization of the dorsal striatum and the importance of this sector of the dopamine system for the learning of complex motor behaviours [27]. Dopaminergic pathways to the ventral striatrum The role of the dopaminergic pathways to the ventral striatum has proved more difficult to unravel. The recognition that the nucleus accumbens is intimately related to other dopaminergically innervated parts of the limbic system (an anatomical axis that was subsequently defined as the ‘extended amygdala’ [28]) led to the proposal that the mesolimbic dopamine pathways are involved in motivation, providing a link between affect and action [29]. Extension of this hypothesis has been dependent on advances in the field of learning theory [30]. Animals learn goal-directed behaviour based on (i) their knowledge of the contingency between their actions and the goal outcomes, and (ii) the value of these outcomes [31]. This learning has been described as a ‘cognitive value system’ guiding behaviour. A second value system [32] operates when reinforcement is experienced that determines how much we ‘like’ the outcome of our behaviour – the term ‘pleasure’ is often used to describe this value [33]. Rats perform instrumental responses to obtain intracranial self-stimulation (ICSS) of anatomically linked brain sites [34], which are designated the neural substrate of the pleasure system. The subsequent realization that these ICSS sites lie on the trajectory of dopamine neurons [35] led to the hypothesis that dopamine has a central role in reward and reinforcement [36]. This simple and appealing hypothesis has been challenged, however, by many experimental findings and by a growing understanding of the multiplicity of processes that underpin associative learning (both instrumental and Pavlovian) [37,38]. Studies involving neurophysiology, in vivo dialysis, local pharmacological manipulations, and lesions have all played a part in clarifying the idea that dopamine lies at the heart of a complex of neural systems, which each contribute to the component processes of reinforcement, motivation and learning [39]. A current synthesis suggests that the dopamine input to the nucleus accumbens core encodes information about the importance or ‘salience’ of events in the world [40], including sensitivity to rewarding [41–43] and aversive [44,45] stimuli, to conditioned reinforcers [46] and to their predictability or novelty [47,48]. The large transient increase in synaptic dopamine release associated with the ‘phasic’ burst firing of dopamine neurons [49] is considered to be the functionally relevant signal at postsynaptic sites encoding reward prediction or incentive salience [50].
190
Review
TRENDS in Neurosciences
Abnormal functioning of this process in schizophrenia could create aberrant perception of novelty and salience, leading to psychotic delusions [40]. The accumbens shell [51–53], by contrast, has a different pattern of neuronal organization and efferent targets, including the A9 mesencephalic dopamine neurons. It has been suggested that this pattern puts the accumbens shell in control of dopaminergic input to wide areas of the striatum, acting to invigorate behaviours coordinated through the accumbens core (goal-directed S– S) and the dorsal striatum (procedural S–R). Indeed, the conventional dorsal versus ventral striatal dissociation is increasingly challenged in favour of a dorsolateral–ventromedial axis with the caudomedial accumbens shell at the extreme of this axis [54]. In this analysis, the dopamine input to both nucleus accumbens and striatum provides a coordinated modulation underpinning goal-directed and procedural learning – and the balance between them – as the animal experiences the changing world and adapts accordingly. Studies have focused on the instrumental learning of natural reinforcers (e.g. food), but of equal significance have been studies of behaviour motivated by the availability of addictive drugs [55–57], which also act through the dopamine systems of the ‘extended amygdala’. The mesolimbic dopamine system projects beyond the nucleus accumbens, and those pathways to the amygdala are crucial for the associative learning (Pavlovian) underlying the affective responses of animals to salient events [58]. Disruption of such associative processes could contribute to the inappropriate affect in schizophrenia and to heightened distractibility in attention deficit hyperactivity disorder (ADHD). Dopaminergic pathways to prefrontal cortex Until recently, dopaminergic projections to the prefrontal cortex, where dopamine D1 receptors predominate, had received little research attention [59]. The activity of neurons in this area has been recorded in monkey brain during performance of a spatial occulomotor-delayed response task [60,61]. Whereas D2 receptor activation was found to correlate with memory-guided saccades [61], D1 agonists potentiated neuronal activity, providing optimal stimulation at these receptors essential to the working memory process [60], and introduced the important concept of the inverted U relationship between the level of brain dopamine activity and function [62]. These results confirmed earlier pharmacological and lesion studies [63] that concluded that dopamine release in prefrontal cortex, acting through D1 receptors, modulates cognitive behaviour (spatial working memory). These findings have had an impact in schizophrenia research, because the cognitive impairments in this disorder are now considered to be the principal debilitating symptom. Existing anti-psychotic drugs successfully control the ‘first rank’ positive symptoms (delusions, hallucinations) but not the cognitive deficit, despite initial hopes for the ‘atypical neuroleptics’. People who possess the Met158 allele of the enzyme catechol-O-methyl transferase have an impaired ability to inactivate dopamine in prefrontal cortex, where this enzyme has an important role. Such gene carriers show www.sciencedirect.com
Vol.30 No.5
impaired cognitive function and an increased risk of developing schizophrenia [64]. Parkinson’s disease The discovery of dopamine and the description of an analytical method for its measurement were followed very quickly by reports of markedly depleted levels of dopamine in the basal ganglia of individuals dying from Parkinson’s disease. Ehringer and Hornykiewicz [65] in Vienna were the first to report such findings in 1960, and Birkmayer and Hornykiewicz [66] published the first positive findings with L-DOPA treatment one year later. Similar results were reported almost simultaneously by Barbeau et al. [67] in Canada. But it took several more years before Cotzias [68] in the USA developed the first practical dosage regime for the routine use of L-DOPA in the treatment of Parkinson’s disease – still one of the major achievements in the rational development of novel therapies for neuropsychiatric diseases. L-DOPA therapy has been further improved by its combination with carbi-DOPA or benserazide to prevent metabolism of L-DOPA in the liver, by the development of slow release formulations allowing more ‘on’ time and fewer ‘off’ periods, and more recently by the advent of various dopamine receptor agonists as supplements to LDOPA or as monotherapy in the early stages of the illness [69]. The influence of heredity in Parkinson’s disease was controversial for many years. But the identification in recent years of mutations in six genes responsible for Mendelian forms of Parkinson’s disease has confirmed the role of genetics in familial forms of the disease [70]. Many unanswered questions remain. For example, why are dopaminergic neurons selectively targeted? And why does the disease become manifest only in old age? The development of powerful new genetic models of Parkinson’s disease in Drosophila and other simpler organisms might help to answer some of these questions [71]. Schizophrenia Whereas basic research revealed a deficit of dopamine in Parkinson’s disease that in turn predicted L-DOPA treatment, in schizophrenia the first effective antipsychotic drugs were discovered by serendipity and it was research into how such drugs acted that led to the ‘dopamine hypothesis’. Van Rossum [72] and Carlsson and Lindqvist [73] were the first to suggest that chlorpromazine might act by blocking receptors for dopamine in the brain, but it was some time before this suggestion could be supported by direct measurements of the effects of chlorpromazine and other neuroleptic drugs on dopamine receptors (see later). Meanwhile, another drug – amphetamine – was providing important clues. Effects of D-amphetamine In developing haloperidol and other new anti-schizophrenic drugs, Janssen et al. [74] in Belgium found empirically that some animal behavioural tests could be used to predict novel anti-schizophrenic drugs. Among the most reliable tests was the ability to block the stimulant actions of amphetamine in animals – particularly blockade of the repetitive stereotyped behaviour elicited by high doses of amphetamine. It also
Review
TRENDS in Neurosciences
became clear that the actions of amphetamine could be attributed to its ability to cause release of dopamine in the brain [75]. Behavioural studies showed that amphetamine-induced stereotypies could be replicated by injection of dopamine into the dopamine-rich basal ganglia of rat brain, and that anti-psychotic drugs were ‘specific antagonists of amphetamine stereotypy’ [76]. Further insight into the importance of the dopamine neurons in the brain in mediating the various behavioural responses to D-amphetamine was provided by experiments in which these neurons were selectively destroyed in different brain regions by local micro-injections of 6-hydroxydopamine. Selective lesions of noradrenaline neurons were found to have little effect on the stimulant actions of Damphetamine, but the stimulant actions were completely absent in animals with selective dopamine lesions [77]. Further studies with 6-hydroxydopamine showed that different groups of dopamine neurons in brain are responsible for the stimulant (running activity) and stereotyped behavioural responses to D-amphetamine. In rats in which the dopamine stores in the striatum were destroyed by local micro-injections of 6-hydroxydopamine, the stereotyped behavioural response to high doses of D-amphetamine was greatly reduced, but the running response remained intact. By contrast, micro-injections of 6hydroxydopamine into the nucleus accumbens abolished the running response to D-amphetamine while leaving the stereotyped behavioural response intact, suggesting that dopamine release in different regions of the brain mediates distinct elements of the behavioural response [78]. Another important observation was that amphetamine could induce a schizophrenia-like psychosis in human volunteers, and could exacerbate psychotic symptoms in individuals with schizophrenia [79]. Although amphetamine-induced psychosis does not completely model the symptoms of schizophrenia, it mirrors some of the so-called ‘first rank’ positive symptoms. The dopamine hypothesis The various above findings provided compelling evidence for a link between brain dopamine and schizophrenic illness and offered further support for the idea that the mode of action of the neuroleptic drugs was as dopamine antagonists. By the early 1970s, some scientists proposed that these emerging discoveries suggested that the underlying abnormality in brain function in schizophrenia might be overactivity of dopamine mechanisms. Matthysse [80] and Snyder et al. [81] reviewed the evidence then available in support of the ‘dopamine hypothesis’. It is worth noting that the discovery of test-tube models to test the binding of neuroleptic drugs to brain dopamine receptors, which provided clear supporting evidence for the dopamine hypothesis, occurred some years after this (see later). The emergence of the ‘dopamine hypothesis’ prompted several laboratories to seek direct evidence for abnormalities in the dopamine system in the brains of schizophrenic individuals (reviewed in Ref. [82]). Early studies concentrated on measurements of neurotransmitters and their receptors in samples of brain tissue obtained after death. Several studies did indeed find increased levels of dopamine and dopamine D2 receptors, but the interpretation www.sciencedirect.com
Vol.30 No.5
191
of these findings proved equivocal because most of the individuals involved in such studies had received longterm treatment with antipsychotic drugs. Animal studies clearly showed that chronic treatment with antipsychotic drugs led to an increase in the density of dopamine receptors in brain, presumably as a compensatory change in response to drug-induced receptor blockade. Subsequent studies used brain imaging methodology to assess brain dopamine receptors in the living human brain. To avoid the above complications, these studies were confined to individuals with schizophrenia who had not received antipsychotic drug treatment. Nevertheless, the results were again ambiguous [82]. More recent imaging studies, however, have lent new support to the dopamine hypothesis. Three separate groups have reported that low doses of D-amphetamine cause an increased release of dopamine in the brains of schizophrenic individuals by comparison with control subjects [82]. Furthermore, when brain dopamine was depleted by administering the synthesis inhibitor a-methyl tyrosine, a significant increase in dopamine D2 receptors could be detected, suggesting that higher levels of dopamine in the schizophrenic brain lead to an increased occupancy of dopamine D2 receptors at baseline, thereby obscuring the true difference in receptor densities that exists [83]. Thus, although static measurements of dopaminergic mechanisms failed to reveal significant abnormalities in schizophrenia, dynamic studies have been more positive. The results suggest that at least the active, florid symptoms of schizophrenia might be associated with an increase in synaptic release of dopamine, together with a possible sensitization to the actions of dopamine [84]. Attention deficit hyperactivity disorder In recent years, there has been a marked increase in the use of dopamine-based psychostimulants to treat children with ADHD [82]. An adult form of ADHD is also now recognized and is treated with the same drugs. The most commonly used is methyl phenidate (Ritalin1). As a potent inhibitor of the dopamine transporter, methyl phenidate potentiates the actions of synaptically released dopamine [82]. Increased release of dopamine in response to the drug has been observed in imaging studies, and was most marked when subjects were asked to undertake a challenging mental arithmetic task as opposed to viewing cards passively [85]. Thus, unlike amphetamine – the other drug commonly used to treat ADHD – methylphenidate does not cause an indiscriminate burst of dopamine release from vesicular stores, but affects only the synaptically released transmitter. This might be an important factor underlying the apparently low risk of developing dependence on methyl phenidate with repeated use [82]. Although the neurobiological basis of ADHD remains poorly defined, the effectiveness of the dopamine-based stimulant drugs in its treatment suggests an underlying dopamine hypofunctional state. Several genetic studies have identified several candidate risk factor genes and consistent evidence exists for an association between ADHD and the four genes encoding the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters [86].
192
Review
TRENDS in Neurosciences
Concluding remarks Dopaminergic neurons represent a tiny proportion of the total neuronal population in the CNS but, through their highly divergent branching networks of fibres, these few cells influence large territories of the brain. Research on dopaminergic mechanisms has played a key part in the modern development of biological psychiatry and has helped to bridge the gap between studies of brain chemistry and higher brain function. The next 50 years will be at least as eventful.
Vol.30 No.5
25
26 27 28 29
References 1 Vane, J.R. et al., (eds) (1960) Ciba Foundation Symposium on ‘Adrenergic Mechanisms’, J&A Churchill 2 Kebabian, J.W. et al. (1972) Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain and its similarity to the ‘dopamine receptor’. Proc. Natl. Acad. Sci. U. S. A. 69, 2145–2149 3 Miller, R.J. et al. (1974) The actions of neuroleptic drugs on dopaminestimulated adenosine cyclic 30 ,50 -monophosphate production in rat neostriatum and limbic forebrain. Mol. Pharmacol. 10, 759–766 4 Creese, I. et al. (1976) Dopamine receptors and average clinical doses. Science 194, 545–546 5 Seeman, P. et al. (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc. Natl. Acad. Sci. U. S. A. 72, 4376–4380 6 Werkman, T.R. et al. (2006) Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol. Disord. Drug Targets 5, 3–23 7 Meltzer, H.Y. (2004) What’s atypical about atypical antipsychotic drugs? Curr. Opin. Pharmacol. 4, 53–57 8 Burris, K.D. et al. (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 302, 381–389 9 Greengard, P. (2001) The neurobiology of slow synaptic transmission. Science 294, 1024–1030 10 Cheramy, A. et al. (1988) Direct and indirect presynaptic control of dopamine release by excitatory amino acids. Amino Acids 14, 63–68 11 Cheramy, A. et al. (1981) Dendritic release of dopamine in the substantia nigra. Nature 289, 537–542 12 Marsden, C.A. et al. (1988) In vivo voltammetry – present electrodes and methods. Neuroscience 25, 389–400 13 Zetterstro¨m, T. et al. (1983) In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after amphetamine. J. Neurochem. 41, 1769–1773 14 Sedvall, G. and Farde, L. (1995) Chemical brain anatomy in schizophrenia. Lancet 346, 743–749 15 Volkow, N.D. et al. (1996) PET evaluation of the dopamine system of the human brain. J. Nucl. Med. 37, 1242–1256 16 Volkow, N.D. et al. (2003) The addicted human brain: insights from imaging studies. J. Clin. Invest. 111, 1444–1451 17 Ungerstedt, U. (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Scand. 367 (Suppl.), 1–48 18 Moore, R.Y. and Bloom, F.E. (1978) Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu. Rev. Neurosci. 1, 129–169 19 Uretsky, N.J. and Iversen, L.L. (1970) Effects of 6-hydroxydopamine on catecholamine containing neurones in the rat brain. J. Neurochem. 17, 269–278 20 Ungerstedt, U. (1976) 6-Hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway: the turning syndrome. Pharmacol. Ther. B 2, 37–40 21 Barnes, T.D. et al. (2005) Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature 437, 1158–1161 22 Gerfen, C.R. et al. (1987) The neostriatal mosaic. II. Patch and matrixdirected mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci. 7, 3915–3934 23 Haber, S.N. (2003) The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 26, 317–330 24 Alexander, G.E. et al. (1990) Basal ganglia–thalamocortical circuits: parallel substrates for motor, occulomotor, ‘prefrontal’ and ‘limbic’ www.sciencedirect.com
30 31 32
33
34
35
36 37 38
39
40 41
42
43
44
45
46
47 48 49
50
functions. In The Prefrontal Cortex: its Structure, Function and Pathology (Uylings, H.B.M. et al., eds), pp. 119–146, Elsevier Bjo¨rklund, A. et al. (1980) Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 199, 307–333 Dunnett, S.B. et al. (2001) Cell therapy in Parkinson’s disease – stop or go? Nat. Rev. Neurosci. 2, 365–369 Do¨bro¨ssy, M.D. and Dunnett, S.B. (2001) The influence of environment and experience on neural grafts. Nat. Rev. Neurosci. 2, 871–879 Heimer, L. et al. (1997) The accumbens: beyond the core–shell dichotomy. J. Neuropsychiatry. Clin. Neurosci. 9, 354–381 Mogenson, G.J. et al. (1980) From motivation to action: functional interaction between the limbic system and the motor system. Prog. Neurobiol. 14, 69–97 Dickinson, A. (1994) . In Animal Learning and Cognition (Mackintosh, N.J., ed.), pp. 45–79, Academic Press Dickinson, A. and Balleine, B. (1994) Motivational control of goaldirected action. Anim. Learn. Behav. 22, 1–18 Balleine, B. and Dickinson, A. (1991) Instrumental performance following reinforcer devaluation dependence upon incentive learning. Q. J. Exp. Psychol. 43, 279–296 Berridge, K.C. and Robinson, T.E. (1998) What is the role of dopamine in reward? Hedonic impact, reward learning or incentive salience?. Brain Res. Rev. 28, 309–369 Olds, J. and Milner, P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427 Crow, T.J. (1972) Catecholamine-containing neurons and electrical self stimulation: a review of some data. Psychol. Med. 2, 414– 421 Wise, R.A. (1978) Catecholamine theories of reward: a critical review. Brain Res. 152, 215–247 Robbins, T.W. and Everitt, B.J. (1996) Neurobehavioural mechanisms of reward and motivation. Curr. Opin. Neurobiol. 6, 228–236 Cardinal, R.N. et al. (2002) Emotion and motivation: the role of the amygdala, ventral striatum and prefrontal cortex. Neurosci. Biobehav. Rev. 26, 321–352 Salamone, J.D. and Corres, M. (2002) Motivational views of reinforcement: implications for understanding the behavioural functions of nucleus accumbens dopamine. Behav. Brain Res. 137, 3–25 Kapur, S. (2004) How antipsychotics become anti-‘psychotic’ – from dopamine to salience to psychosis. Trends Pharmacol. Sci. 25, 402–406 Kelley, A.E. (2004) Ventral striatum control of appetitive motivation in ingestive behaviour and reward-related learning. Neurosci. Biobehav. Rev. 27, 765–776 Kelley, A.E. et al. (1997) Response–reinforcement learning is dependent on NMDA receptor activation in the nucleus accumbens core. Proc. Natl. Acad. Sci. U. S. A. 94, 12174–12179 Corbit, L.H. et al. (2001) The role of the nucleus accumbens in instrumental conditioning: evidence of a functional dissociation between accumbens core and shell. J. Neurosci. 21, 3251–3260 Reynolds, S.M. and Berridge, K.C. (2002) Positive and negative motivation in nucleus accumbens shell: bivalent rostrocaudal gradients for GABA-elicited eating, taste ‘liking/dislike’ reactions, place preference/avoidance and fear. J. Neurosci. 22, 7308–7320 Salamone, J.D. (2004) The involvement of nucleus accumbens dopamine in appetitive and aversive motivation. Behav. Brain Res. 61, 117–133 Parkinson, J.A. et al. (1999) Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behaviour and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J. Neurosci. 19, 2401– 2411 Schultz, W. (2000) Multiple reward signals in the brain. Nat. Rev. Neurosci. 1, 199–207 Schultz, W. (2002) Getting formal with dopamine and reward. Neuron 36, 241–263 Grace, A.A. (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 Waelti, P. et al. (2001) Dopamine responses comply with basic assumptions of formal learning theory. Nature 412, 43–48
Review
TRENDS in Neurosciences
51 Zaborszky, L. et al. (1985) Cholecystokinin innervation of the ventral striatum: a morphological and radioimmunological study. Neuroscience 14, 427–453 52 Usuda, I. et al. (1998) Efferent projections of the nucleus accumbens in the rat with special reference to subdivision of the nucleus: biotinylated dextran amine study. Brain Res. 797, 73–93 53 Voorn, P. et al. (1989) The compartmental organization of the ventral striatum of the rat: immunohistochemical distribution of enkephalin, substance P, dopamine and calcium-binding protein. J. Comp. Neurol. 289, 189–201 54 Voorn, P. et al. (2004) Putting a spin on the dorsal–ventral divide of the striatum. Trends Neurosci. 27, 468–474 55 Di Chiara, G. (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain Res. 137, 75– 114 56 Robinson, T.E. and Berridge, K.C. (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291 57 Everitt, B.J. et al. (1999) Associative processes in addiction and reward. The role of amygdala–ventral striatal subsystems. Ann. N. Y. Acad Sci. 877, 412–438 58 Rosenkranz, J.A. and Grace, A.A. (2002) Dopamine-mediated modulation of odour-evoked amygdala potentials during Pavlovian conditioning. Nature 417, 282–287 59 Sawaguchi, T. and Goldman-Rakic, P.S. (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251, 947–950 60 Williams, G.V. and Goldman-Rakic, P.S. (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572– 575 61 Wang, M. et al. (2004) Selective D2 receptor actions on the functioning circuitry of working memory. Science 303, 853–856 62 Desimone, R. (1995) Is dopamine a missing link? Nature 376, 549–550 63 Goldman-Rakic, P.S. (1992) Dopamine mediated mechanisms of the prefrontal cortex. Semin. Neurosci. 4, 149–159 64 Tunbridge, E.M. et al. (2006) Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol. Psychiatry 60, 141–151 65 Ehringer, H. and Horynkiewicz, O. (1960) Verteilung von noradrenalin und dopamine (3-hydroxtyramin) im gehirn des menschen und ihr verhalten bei erkankungen des extrapyamidalen systems. Klin. Wschr. 38, 1236–1239 66 Birkmayer, W. and Hornykiewicz, O. (1961) Der L-3,4-dioxyphenylalanin (L-DOPA) – effect bei der Parkinson-akinese. Wien. Klin. Wschr. 73, 787– 788 67 Barbeau, A. et al. (1962) Les catecholamines dans la maladie de Parkinson, In Monoamines et Syste`me Nerveux Central, pp. 247–262, Georg et C, Geneva 68 Cotzias, G.C. (1968) L-DOPA for Parkinsonism. N. Engl. J. Med. 278, 630
Vol.30 No.5
69 Thomson, F. et al. (2001) Parkinson’s disease: treatment. Pharm. J. 267, 600–613 70 Gosal, D. et al. (2006) Parkinson’s disease: the genetics of a heterogeneous disorder. Eur. J. Neurol. 13, 616–627 71 Feany, M.B. and Bender, W.W. (2000) A Drosophila model of Parkinson’s disease. Nature 404, 394–398 72 Van Rossum, J.M. (1966) The significance of dopamine-receptor blockade for the action of neuroleptic drugs. Arch. Int. Pharmacodyn. Ther. 160, 492–494 73 Carlsson, A. and Lindqvist, M. (1963) Effect of chlorpromazine or haloperidol on the formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. (Kbh.) 20, 140–144 74 Janssen, P.A.G. et al. (1965) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Part I. Neuroleptic activity spectra for rats. Arzn. Forsch. 15, 104–117 75 Moore, K.E. (1977) The actions of amphetamine on neurotransmitters: a brief review. Biol. Psychiatry 12, 451–462 76 Randrup, A. and Munkvad, I. (1970) Biochemical, anatomical and psychological investigations of stereotyped behaviour induced by amphetamines. In Amphetamine and Related Compounds (Costa, E. and Garratini, S., eds), pp. 695–713, Raven Press 77 Creese, I. and Iversen, S.D. (1974) The role of forebrain dopamine systems in amphetamine induced stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine. Psychopharmacology (Berl.) 39, 345–357 78 Kelly, P.H. et al. (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res. 94, 507–522 79 Angrist, B. and Sudilovsky, A. (1978) Central nervous system stimulants: historical aspects and clinical effects. In Handbook of Psychopharmacology (Vol. 11) (Iversen, L.L. et al., (eds)), pp. 99–165, Plenum Press 80 Matthysse, S. (1973) Antipsychotic drug actions: a clue to the pathology of schizophrenia? Fed. Proc. 32, 200–205 81 Snyder, S.H. et al. (1974) Drugs, neurotransmitters and schizophrenia. Science 184, 1243–1245 82 Iversen, L.L. (2006) Speed, Ecstasy, Ritalin: the Science of Amphetamines, Oxford University Press 83 Abi-Dargham, A. et al. (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 97, 8104–8109 84 Seeman, P. et al. (2005) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc. Natl. Acad. Sci. U. S. A. 102, 3513–3518 85 Volkow, N.D. et al. (2004) Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am. J. Psychiatry 161, 1173–1180 86 Bobb, A.J. et al. (2005) Molecular genetic studies of attention deficit hyperactivity disorder 1991–2004. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 132, 109–125
Endeavour Coming soon in the quarterly magazine for the history and philosophy of science: Earthquake theories in the early modern period by F. Willmoth Science in fiction - attempts to make a science out of literary criticism by J. Adams The birth of botanical Drosophila by S. Leonelli
Endeavour is available on ScienceDirect, www.sciencedirect.com www.sciencedirect.com
193