Dopamine: 50 years in perspective

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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

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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

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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].

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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

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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

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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

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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].

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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.

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