The functional role of mesotelencephalic dopamine systems.

Biol. Rev. (1992),67, pp. 491-518 Printed in Great Britain

T H E FUNCTIONAL ROLE OF MESOTELENCEPHALIC DOPAMINE SYSTEMS BY STEPHEN B. D U N N E T T AND TREVOR W. ROBBINS

Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, U.K. (Received

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October 1991 ; revised 6 July 1992; accepted 7 July 1992) CONTENTS

I. Introduction . . . . . . . . . . . . 11. Motor effects of dopaminergic drugs and lesions . . . . . ( I ) Akinesia associated with catecholamine depletions . . . . (2) Stimulant drugs: locomotor activity and stereotypy . . . (3) The nigrostriatal rotation model . . . . . . . 111. Motivational effects of hypothalamic and dopaminergic lesions . ( I ) Effects of lateral hypothalamic and nigrostriatal lesions . . (2) Stimulus-bound behaviours . . . . . . . . (3) Dopamine and stress . . . . . . . . . IV. Sensorimotor interpretations of hypothalamic and dopaminergic lesions. ( I ) Sensorimotor test batteries and neglect . . . . . . (2) Sensorimotor interpretations of eating and rotation deficits . . V. Cognitive effects of neostriatal and dopaminergic lesions . . . VI. Role of dopaminergic systems in response selection . . . . ( I ) Response initiation following nigrostriatal lesions . . . . (2) Response switching and incentive motivation following ventral striatal VII. An integrated role for forebrain dopamine systems . . . . V I I I. Acknowledgements . . . . . . . . . . IX. References . . . . . . . . . . . .

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I. INTRODUCTION

The availability for three decades of sensitive neuroanatomical, electrophysiological, pharmacological and biochemical tools to monitor and manipulate the functional activity of central dopamine neurons has resulted in the forebrain dopamine systems being perhaps the most extensively studied functional pathways in the mammalian brain. In the present review we seek to illustrate the behavioural effects of a wide variety of manipulations that have been employed to study the functional role of forebrain dopamine systems. Fig. I and Table I outline the basic anatomical distribution of these systems in the rat brain: the major dopamine cell groups in the substantia nigra and ventral tegmental area of the brain stem which then extend their axons to provide a rich dopamine innervation of circumscribed areas of the forebrain in particular in the neostriatum, the ventral striatum and particular areas of the limbic cortex (Bjorklund & Lindvall, 1982). The analysis of dopamine organization and function is not merely an academic question. The demonstration in the early 1960s of a dopaminergic deficiency in Parkinson's disease rapidly led to the introduction of L-DOPA as an effective

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Fig. I , Schematic diagram of the anatomical subdivisions of the major forebrain dopamine (DA) systems, viewed in a lateral section of the rat brain (see also Table I). Abbreviations: S N , substantia nigra (frequently designated as cell groups 4 8 and A9); V T A , the ventral tegmental area (frequently designated as cell group A I O ) ; AIFB, medial forebrain bundle (including the ascending D A axons of both nigrostriatal and mesocorticolimbic systems); h-S, neostriatum (subdivided into the caudate and putamen in man and monkeys but not in rats); NA, nucleus accumbens; OT, olfactory tubercle (ventral striatal targets of the mesocorticolimbic D A system); P F C , prefrontal cortex; AC, anterior cingulate cortex; A , amygdala; S, septum (less dense targets of the mesocorticolimbic DA system).

Table I. Anatomical subdivisions of forebrain dopamine systems'* Nigrostriatal system

llesocorticolimbic system (mesolimbic subdivision)

Llesocorticolimbic system (mesocortical subdivision) Ventral tegmental area (XIO) 3Iedial forebrain bundle Prefrontal neocortex Cingulate cortex Xmygdala Lateral septum Coping with stress/ cognitive processes

Cell bodies Axon bundles Target areas

Substantia nigra (A8, A9) hIedial forebrain bundle Dorsal (or Neo-) striatum Caudate nucleus Putamen

Ventral tegmental area ( A I o ) Medial forebrain bundle Ventral striatum Nucleus accumbens Olfactory tubercle

Functions ?

Sensorimotor integration/ initiation of action

Incentive motivation/ response switching

* T h e small tuberoinfundibular system of the ventral hypothalamus, which has probable neuroendocrine functions, and the small dopamine neurons of the olfactory bulb are not considered further in the present review.

replacement therapy for patients with this neurodegenerative disorder. However, longterm administration of L-DOPA and other dopaminergic drugs are associated with a number of serious problems (such as an insidious loss of benefit, and the progressive appearance of severe fluctuations - 'on-off' swings - in the response to the drugs (Marsden & Parkes, 1977) that are in urgent need of further elucidation. More recently, the advent of the first clinical trials of transplants of dopamine-rich neural tissues into the parkinsonian brain has achieved limited success (Lindvall, I 989 ; Quinn, Dunnett & Oertel, 1989), but the development of improved techniques requires a more detailed analysis of the degree to which grafted dopamine neurones can become integrated functionally in the host brain in a manner similar to the dopamine neurones

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of the intact nigrostriatal system (Dunnett, Rogers & Richards, 1989). Moreover, the neuroleptic drugs appear to exert their pharmacological effects by blocking dopamine and noradrenaline receptors. Since the clinical potency of these drugs in the treatment of schizophrenia appears to correlate most closely with their affinity for the dopamine receptor (Seeman, Lee, Chang-Wong & Wong, 1976), this may suggest an involvement of central dopaminergic systems in the pathophysiology of schizophrenia. However, the exact mode of action of neuroleptic drugs is still far from being well understood, either in pharmacological or in behavioural terms. The accumulated literature on the functional effects of dopaminergic manipulations in rodents and other animals is vast, and it would require a book (Mason, 1984) or an encyclopaedic review (Le Moal & Simon, 1990) to attempt a comprehensive survey. Additionally, current conceptions of central dopamine function are the outcome of several initially independent but subsequently converging lines of research, such as the biochemical and pharmacological properties of catecholaminergic drugs on the one hand, and the neural substrates of the motivational phenomena associated with hypothalamic manipulations on another. We therefore offer an overview of each of these strands of research, prior to the consideration of contemporary studies that attempt to provide an integrated analysis of central dopamine function. We will concentrate on the effects of central dopamine depletion induced by lesions, but will also refer to studies employing other techniques, such as intracerebral infusion of dopaminergic drugs, where appropriate. 11. MOTOR EFFECTS OF DOPAMINERGIC DRUGS AND LESIONS

( I ) Akinesia associated with catecholamine depletions

Drugs that deplete central catecholamines, such as reserpine or a-methyl tyrosine, induce akinesia and (at higher doses) catalepsy, the persistent assumption of an abnormal posture. These effects can be reversed by D,L-DOPA(Carlsson, Lindqvist & Magnusson, I 957 ; Ahlenius, And& & Engel, 1973). These pharmacological treatments each influence both dopamine and noradrenaline, but Carlsson (1959) was the first to suggest that the akinetic effect of anticatecholaminergic drugs was attributable to the depletion of dopamine rather than noradrenaline in the central nervous system. He reached this conclusion on the basis of two indirect arguments: ( a ) antagonism of the reserpine effect by DOPA is accompanied by marked increases in brain dopamine levels with little effect on noradrenaline concentration, and ( b ) the corpus striatum, which as part of the extrapyramidal motor systems might be considered to be involved in motor effects of the drug, contains high levels of dopamine but very little noradrenaline. The attribution of particular functional consequences to the manipulation of an identified central neurotransmitter system was at first received with considerable scepticism (Carlsson, I 987), but subsequent studies have amply confirmed that initial tentative hypothesis. Thus, neuroleptic drugs which provide a relatively selected blockade of central dopamine receptors, such as spiroperidol or haloperidol, readily induce catalepsy in rats and other mammals (Costal1 & Naylor, 1973 ; de Ryck, Schallert & Teitelbaum, 1980; Sandberg, 1980), whereas antagonists of the a or p noradrenergic receptors, such as phentolamine or propranolol, produce no marked effects on motor activity. In parallel, it has been found that injection of the catecholamine toxin 6-

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hydroxydopamine (6-OHDA) into the substantia nigra of rats, depleting the forebrain of both noradrenaline and dopamine, results in a decline in spontaneous locomotor activity in rats (Creese & Iversen, 1975). -4 similar level of hypokinesia results if selective lesions of the dopamine neurons are obtained following protection of the noradrenaline neurons from 6 - O H D A toxicity by pretreatment with the noradrenergic uptake inhibitor desmethylimipramine ( D M I ; Kelly & Iversen, I 976), whereas selective lesions of the ascending noradrenergic fibre systems by injection of 6-OHDA into midbrain sites caudal to the dopamine cell bodies produce no significant changes in spontaneous activity (Creese & Iversen, 1975). (2)

Stimulant drugs : locomotor actiaity and stereotypy

Drugs that enhance dopaminergic transmission in the brain, such as amphetamine, L-DOPA, cocaine or apomorphine, have the converse effect to those inducing catecholamine depletion, namely motor activation. I n rats, which will provide the focus of the present review, motor activity has been variously measured by observation in open fields, and by automated recording in photocell cages, running wheels, jiggle and tilt cages, and ‘Animex’ radar devices. These various types of apparatus monitor somewhat different elements of motor behaviour, but direct comparison generally yields good correlation between the alternative measures, of which the use of photocell cages is perhaps the simplest and most reliable (see Robbins, 1977, for review). T h e prototypical stimulant drug is amphetamine, which exerts its pharmacological action by stimulating release of the catecholamines (both dopamine and noradrenaline) from the presynaptic nerve terminal and by inhibiting their reuptake back into the terminal after release. These two mechanisms both work on the presynaptic terminal so as to increase the level of neurotransmitter in the synaptic cleft and thereby enhance stimulation of the postsynaptic receptors. Low to moderate doses of amphetamine induce progressively greater behavioural activation of the recipient, which in rats is expressed as whole-body locomotion. However, the relationship is not monotonic ; rather the dose-response relationship for activity yields an inverse-U ’-shaped function, with locomotor activity declining at higher doses of amphetamine, associated with the progressive appearance of stereotypic behaviours (Randrup & Munkvad, I 967 ; Fog, 19-72). Stereotypy in response to amphetamine has been seen in all mammalian species studied, including man, and can be defined as the repetition of invariant sequences of behaviour, the form of which will depend on the species and also the drug dose. T h e frequently localized and intense nature of stereotyped behaviour is incompatible with whole-body locomotor activity, so that the phenomenological transition from locomotion to stereotypy with increasing doses of amphetamine or other stimulant drugs can be interpreted as the result of behavioural competition. Lyon & Robbins (1975) developed the idea of behavioural competition to provide a general hypothesis accounting for the effects of stimulant drugs and, in particular, the nature of stereotypy. T h a t review of the literature led to the suggestion that the major effect of amphetamine is to produce a general stimulation of all response tendencies. However, not all of these tendencies can be expressed in observable behaviour at the same time. T h e effect of this becomes apparent at low doses of stimulant drugs by a shortening of particular behaviour tendencies as the animal switches between competing responses. Concomitantly, the expression of longer and more complex response


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sequences becomes inhibited by competition from shorter and simpler responses, which consequently come to predominate. Thus, stereotypy is observed as an increased rate of responding within a progressively reduced number of short repetitious response categories. In humans, amphetamine stereotypies are expressed as much in repetitious thoughts and ideas as in overt behaviours. Typically, in the rat, the responses that predominate are sniffing, licking and gnawing (e.g. Fray, Sahakian, Robbins, Koob & Iversen, 1980),but in other species, such as primates, repetitive picking or manipulative movement may be more obvious. It is important to stress that stereotypy is a description of the nature of behaviour, not a specific response itself. The repetitive aspects of stereotypy provide as many clues to the functions of striatal dopamine systems as the fact that, in the rat, sniffing is a response that commonly becomes stereotyped. The types of response elicited may reflect such factors as the topographic control of different response classes by different sub-regions of the striatum (see below), whereas it is the repetitive nature of the behaviour that provides a direct expression of the elevated dopaminergic activity. The majority of the stimulant effects of the amphetamines appear to be dependent on the integrity of dopaminergic rather than noradrenergic systems. Thus, Creese & Iversen (1975) found that nigral 6-OHDA lesions, which depleted both forebrain dopamine and noradrenaline, blocked both the locomotor activation induced by low doses of amphetamine and the stereotypy induced by higher doses. Protection of noradrenergic neurons with D M I did not reduce the effectiveness of 6-OHDA. By contrast, lesions located caudal to the substantia nigra, thereby producing extensive depletions of forebrain noradrenaline but not of dopamine, had little effect on the stimulant effects of amphetamine. These results together suggest a dopaminergic substrates for both the locomotor and the stereotypic effects of amphetamine. Nevertheless, selective lesions of forebrain catecholamine projections have suggested some dissociations in the neural substrates subserving different classes of response induced by stimulant drugs. For example, Kelly et al. (1976) compared the effect of 6OHDA injections in different dopaminergic terminal regions (see Fig. I ) . Lesions of the nucleus accumbens blocked amphetamine-induced locomotor activation whilst having no effect on drug-induced stereotypy. By contrast, neostriatal lesions gave the opposite profile, having no effect on the activity response to a low dose of amphetamine but attenuating the stereotypy induced by a higher dose. When the animals were given a high dose of amphetamine, the control rats exhibited relatively low levels of locomotor activity, presumably as a result of competing stereotyped behaviour, whereas the rats with neostriatal lesions showed a dramatic increase in activity. Thus, following loss of competing stereotypic responses, increasing activation of the nucleus accumbens is expressed by a monotonic increase in locomotion in response to increasing doses of amphetamine (Joyce & Iversen, I 984). Post-synaptic dopamine receptor agonists such as apomorphine induce similar activational changes in rats to presynaptic stimulants such as amphetamine. Thus, moderate doses induce a degree of locomotor hyperactivity which becomes progressively transformed to focused stereotypy at higher doses. However, there are two important differences. Firstly, the locomotor dose-response curve to apomorphine is triphasic, with very low doses inducing an inhibition of activity levels. Carlsson and others (Carlsson, I 975 ; Ungerstedt, Herrera-Marschitz, StHhle & Zetterstrom, I 982)

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have interpreted these effects as reflecting an action of the drug at presynaptic ‘ autoreceptors ’. These presynaptic receptors are considered to be inhibitory, to provide a negative feedback mechanism for autoregulation of dopamine release at the level of the terminal itself, and to be sensitive to doses of the agonist below those which are effective postsynaptically. Secondly, lesions which destroy dopaminergic neurons leave the dopamine receptors on the postsynaptic neurons intact, and these receptors develop compensatory ‘ supersensitivity ’ to agonist molecules. Pharmacological analysis suggests that the phenomenon of supersensitivity reflects an increase in the number rather than in the binding affinity of the receptors (Creese, Burt & Snyder, 1977). Behaviourally, the effects of lesions are to enhance the dopamine-dependent responses to low doses of apomorphine, in contrast to abolishing the stimulant effects of presynaptic drugs such as amphetamine. Thus, for example, Kelly, Seviour & Iversen (1975) found that the locomotor activity induced by apomorphine was enhanced by accumbens lesions, whereas stereotypy was enhanced by neostriatal lesions. T h e complexity of the behavioural effects of dopamine agonists has been increased by the discovery of different classes of dopaminergic receptors, termed D, and D,, as defined by the effects of specific agonists (Clarke & White, 1987). Apomorphine has affinity for both types of receptor, whereas drugs such as SKF 38393 (D,) and RU 24213 (D,) have more selective affinity. Initially it was thought that the D, (nonadenylate cyclase linked) receptor was the main site of elicitation of behavioural effects in response in released dopamine, but more recent studies have shown a synergy of action of D, and D, receptors, at least for the induction of stereotyped forms of behaviour (Molloy & Waddington, 1986; Waddington, 1986). This synergy may reflect a direct coupling of D, and D, receptors in the caudate-putamen (Kelly & Nahorski, 1986). T h e lack of such direct coupling in the ventral striatum may account for the lack of reports of synergy for some of the locomotor effects of DA agonists. T h e physiological and functional significance of the D,-D, receptor coupling and synergetic response in the neostriatum is at present completely unknown, and the entire issue of the role of DA receptors has recently been complicated by the discovery of other (D3, D, and D5) subtypes, which have been defined primarily by molecular cloning and sequencing of the novel receptors (Sokoloff, Giros, Martres, Bouthenet & Schwartz, 1990;Sunahara, Guan, O’Dowd, Seeman, Laurier, Ng, George, Torchia, Van To1 & Niznik, 1991 ; Van Tol, Bunzow, Guan, Sunahara, Seeman, Niznik & Civelli, 1991). At present, selective drugs which stimulate or block each of these novel receptors individually are not available, but their development would provide powerful new tools to investigate the precise contribution of pharmacologically specified subdivisions of the forebrain dopamine systems to the functional components of behaviourial activation. Overall, the neuropharmacological elucidation of the mechanisms involved in the induction of locomotor and stereotyped responses by dopaminergic drugs has had considerable success in demonstrating behavioural correlates of central dopaminergic activity. However, we are still ignorant of the type of process or the nature of the environmental conditions that normally evoke changes in dopaminergic activity in the behaving animal. T h e high levels of release of striatal dopamine induced by standard doses of amphetamine probably represent a pathological exaggeration of normal


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processes, whereas only very low doses of the drug may actually mimic more naturally occurring circumstances. ( 3 ) The nigrostriatal rotation model

Unilateral lesions of the ascending dopamine systems induce a motor asymmetry that is characterised by an acute postural bias to the side of the lesion when the animal is quiescent, and turning in circles (‘rotation’) when the animal is activated. The rotation syndrome was first described by AndCn, Dahlstrom, Fuxe & Larsson (1966) in response to electrolytic lesions of the substantia nigra, but it has been most extensively studied following selective unilateral 6-OHDA lesions of the nigrostriatal system. Ungerstedt ( I 97 I a, b) provided the first detailed description of the response of rats with nigrostriatal lesions following activation with dopaminergic drugs. In particular, he found that stimulant drugs such as amphetamine enhance the animals’ spontaneous ipsilateral bias to induce turning at a rate of 5-15 turns per minute for the 3-4 hour duration of drug action. By contrast, dopamine receptor agonists such as apomorphine result in contralateral turning. This difference can best be interpreted in terms of the site of action of the two classes of drug. Thus, amphetamine acts to stimulate dopamine release from the presynaptic nerve terminals, which remain only on the intact side. This results in a functional activation which is restricted to the intact striatum and a corresponding rotation away from the intact side, i.e. in the direction ipsilateral to the lesion. Conversely, very low doses of apomorphine, below the threshold for action at normal receptors, nevertheless can stimulate supersensitive receptors denervated of their dopamine inputs. This results in a preferential activation on the lesioned side and a corresponding rotation in the opposite direction, i.e. contralateral to the lesion. The rotation response in rats with nigrostriatal lesions has been widely used as a screen for effective drugs that act at central dopamine receptors (Pycock, 1980), at least in part because the response is so easy to quantify as a result of the introduction of a simple procedure for automation of the monitoring of rats’ rotational behaviour (Ungerstedt & Arbuthnott, 1970). It has become clear that the phenomenon of rotation is dependent on recruitment of dopamine projections to the ventral striatum (in particular the nucleus accumbens) as well as to the dorsal neostriatum. Although direct activation of striatal receptors by local injection of dopamine or amphetamine into the dorsal neostriatum can induce postural bias, in particular in the head and neck, to the contralateral side (Ungerstedt, Butcher, Butcher, Anden & Fuxe, 1969; Costal1 & Naylor, 1974), pronounced rotation does not result. Rather, Kelly & Moore (1976; see also Pycock & Marsden, 1978) proposed that rotation is the joint consequence of postural bias derived from dopaminergic asymmetry in the neostriatum and locomotor activation associated with non-lateralized dopaminergic stimulation of the ventral striatum/nucleus accumbens. In an elegant series of experiments, they showed that rats with unilateral striatal lesions alone would rotate ipsilaterally to amphetamine but were unresponsive to apomorphine, whereas when the striatal lesion was combined with bilateral lesions of the nucleus accumbens the animals would rotate contralaterally to a low dose of apomorphine but not to amphetamine. These observations were interpreted as indicating that amphetamine will induce an ipsilateral bias and apomorphine a contralateral bias (via stimulation of the intact and lesioned neostriatum, respectively), but the respective bias

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is only expressed as rotation when associated with locomotor activation (dependent on intact dopaminergic terminals in the nucleus accumbens for a response to amphetamine, but on lesions to induce receptor supersensitivity for a response to a low dose of apomorphine). T h e mechanism by which asymmetry in the dopaminergic activation of striatal neurons becomes translated into the motor response of turning remains mysterious. T h e effective pathways appear to pass via the substantia nigra and superior colliculus to brainstem motor regions (Kilpatrick, Collingridge & Starr, I 982; Leigh, Reavill, Jenner & Marsden, I 983), rather than via pallido-thalamo-cortical convergence onto pyramidal motor pathways. Nevertheless, how this descending activation or disinhibition from both dorsal and ventral striatal outflows becomes translated into a coordinated contralateral turning is unknown. Additionally, the functional significance of rotational behaviour is unclear. Hypotheses interpreting rotation in terms of sensory neglect or impairment in the initiation of action will be considered further below. 111. MOTIVATIONAL EFFECTS OF HYPOTHALALIIC AND DOPXLIINERCIC LESIONS

( I ) EfSects of lateral hypothalamic and nigrostriatal lesions T h e second field of research that has influenced contemporary views on the function of central dopaminergic systems arose from the study of hypothalamic mechanisms of motivational control. Anand & Brobeck (195 I ) first described how lesions of the lateral hypothalamus (LH) produced aphagia a total cessation of eating - to the point where an animal will die of starvation unless maintained by tube feeding. T h e y attributed the deficit to disruption of a central ‘hunger’ centre. It soon became apparent that the LH syndrome reflected a more general motivational impairment, involving deficits in drinking (adipsia), generalized motor activity (akinesia), sexual and exploratory behaviours - in fact, deficits in any class of responding that involved voluntary, goaidirected action (Teitelbaum & Stellar, 1954; Teitelbaum & Epstein, 1962; Levitt %2 Teitelbaum, 1975). Rats with LH lesions that are tube-fed through the acute phase of the syndrome will recover to the point of being able to maintain themselves on dry food and water (Teitelbaum & Epstein, I 962). However, they remain permanently deficient in their responses to physiological disturbances of fluid or metabolic balance, such as intracellular dehydration, extracellular dehydration or hypoglycaemia induced by peripheral injections of hypertonic saline, colloids or insulin, respectively (Teitelbaum & Epstein, 1962; Marshall & Teitelbaum, 1974). A number of early studies cautioned that LH lesions disrupt multiple fibre systems running through the lateral hypothalamic area in the medial forebrain bundle, such that damage to these fibre systems rather than to intrinsic hypothalamic nuclei may account for some features of the syndrome (Morgane, 1961; Lyon, Halpern & Mintz, 1968). T h e first direct evidence for this possibility was provided by Ungerstedt ( I 970, 197I c ) who showed that bilateral 6 - O H D A lesions of the nigrostriatal dopamine pathways reproduce the functional deficits of the LH syndrome remarkably closely. T h u s , injection of the toxin anywhere along the path of the ascending dopamine fibres produces aphagia, adipsia and akinesia. Ungerstedt suggested that the syndrome is in large part attributable to denervation of forebrain dopamine systems rather than to disruption of intrinsic hypothalamic circuits. T h i s first report was soon confirmed in several other laboratories employing a variety of intracerebral and intraventricular ~


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routes of 6-OHDA administration (Zigmond & Stricker 1972; Fibiger, Zis & McGeer, I 973 ; Marshall, Richardson & Teitelbaum, I 974; Stricker & Zigmond, I 974). Although the lesions depleted both dopamine and noradrenaline in most of these early studies, Stricker & Zigmond (I 974) showed that 6-OHDA produced equally profound deficits on eating and drinking when the rats were pre-treated with DMI to protect the noradrenergic system, suggesting that the dopaminergic denervation is the primary cause of the syndrome. Many of the characteristic features of the L H syndrome are reproduced in dopamine denervated rats : the acute symptoms undergo gradual recovery in a relatively standard sequence of stages if the animals are maintained by tube feeding, and they show the same chronic deficits in compensatory responding to physiological challenges that disturb metabolic and fluid balance (Fibiger et al., 1973; Marshall et al., 1974; Stricker & Zigmond, 1974). However, the effects of the two lesions differ in several important respects. For example, EEG measurements indicate a degree of somnolence in the acute phase following LH lesions that are not seen in rats with 6-OHDA lesions. More critically, whereas an effective electrolytic lesion of the LH may only deplete forebrain dopamine levels by 50-60 yo,a selective dopamine denervation made by 6-OHDA must be in excess of 90-95 Yo in order to induce a comparable disturbance of food and water intake (Zigmond & Stricker, 1972). This suggests that damage of intrinsic hypothalamic cells does contribute to the syndrome, and this is confirmed by more recent studies of selective lesions of intrinsic hypothalamic neurons using neurotoxic amino acids. Thus, kainic or ibotenic acid injected bilaterally in the L H area produces mild aphagia and adipsia, and a more severe chronic disturbance of the animals’ capacity to respond to physiological challenges (Grossman, Dacey, Halaris, Collier & Routtenberg, I 978 ; Stricker, Swerdlow & Zigmond 1978; Winn, Tarbuck & Dunnett, 1984). It is not, however, necessary to conclude that the LH and 6-OHDA syndromes are independent. Rather, as emphasized by Wright, Tulloch & Arbuthnott ( I 980), the L H has extensive efferent connections with the pars reticulata of the substantia nigra, so that the two lesion syndromes reflect disruption of serial stages through which motivational status influences the selection of appropriate compensatory responses (Winn et al., I 984). (2) Stimulus-bound behaviour Hess (1928, 1957) first described in detail how electrical stimulation of the hypothalamus elicited aggressive attack behaviour in cats. Subsequent studies have revealed that stimulation of lateral hypothalamic areas via implanted electrodes can induce a wide variety of motivated behaviours, such as attack, freezing, locomotion, eating or drinking. These observations were initially interpreted in terms of experimental activation of specific neural centres in the hypothalamus for the central representation of discrete motivational drive states, such as anger, fear, hunger of thirst. However, Valenstein (1969; Valenstein, Cox & Kakolewski, 1970) found that in any particular animal, stimulation at different electrode placements would all yield the same ‘ stimulus-bound ’ behaviour, dependent only on the available goal objects. If the preferred goal object was removed, the rat would change its apparently motivated responding to an alternative available goal-object. Moreover, Bachus & Valenstein ( I 979) showed that the behavioural responses that were elicited in a particular animal from a particular electrode placement were maintained when small electrolytic lesions

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were made at the stimulating electrode tip, the only change being an increase in the stimulation threshold required to elicit the response. These observations appear incompatible with the notion that hypothalamic stimulation activates discrete neural centres o r circuits involved in distinct motivational processes. Rather, Valenstein and colleagues stressed the lack of response specificity and proposed that the effect of hypothalamic stirnulation is t o increase the expression of any species-specific motivated behaviour, akin to the classic Hullian notion of an increase in generalized Drive (Bolles, I 97 j ) . T h e particular behavioural responses observed will then depend primarily upon the stimulus objects that are available for the animal to act on in its environment and on the individual animal’s reinforcement historj-. Further evidence for the lack of specificity in stimulus-bound behaviour comes from the observation that other extrinsic stressors, such as mild tail-pinch, activate the animal and induce eating, gnawing or licking behaviours similar to those seen under hypothalamic stimulation (Antelman & Szechtman, I 975). Moreover, although the effects may not be specific to discrete hypothalamic circuits, stimulus-bound behaviour does appear to be dependent upon the integrity of the nigrostriatal dopamine sj-stem, and is abolished by intracerebral 6 - O H D A injections or dopamine receptor blockade, whether elicited by hypothalamic stimulation (Phillips & Fibiger, I 976) or tail-pinch (Antelman, Szechtman, Chin & Fisher, 1975). T h u s , studies of hypothalamic involvement in motii7ational control, based on both lesion and stimulation methodologies, have implicated forebrain dopamine systems in the regulation of motivated behaviour. I n particular, it appears that enhancement of forebrain dopamine systems results in a behavioural activation, increasing the tendency for the animal to respond to all salient internal and external motivational stimuli, thus resembling the behavioural response to amphetamine (see Section I1 . z ) . T h e response choice is selected from the species-specific repertoire, as modified by past experience and learned associations between available goal objects (the external stimuli) and the animal’s needs (the internal stimuli). An implicit assumption in such a formulation is that the animal’s needs, such as a state of food deprivation, actively increase activity in the forebrain dopamine systems and thereby recruit the state of behavioural activation. Direct evidence of this relationship remains lacking, but it is clear that a variety of stressors, including food deprivation, can elevate forebrain dopamine activity. (3) Doparnine and stress Stress is a vague term which encompasses a variety of environmental situations. Previous biochemical observations have suggested a specific role for the mesocortical (as opposed to mesolimbic or mesostriatal, see Fig. I ) components of the forebrain dopamine projections in the response to stress (Thierry, Tassin, Blanc & Glowinski, 1976;Blanc, Herve, Simon Lisoprawski, Glowinski & Tassin, 1980; Bannon and Roth, 1983). HoLvever, more recent studies using in &o monitoring techniques have indicated that changes in dopamine metabolism can occur in each of these dopamine terminal regions (Hefner, Hartman & Seiden, 1980; Keller, Stricker & Zigmond, 1983; Knott, Brannan, Andrews, Togasaki, Young, Maker & Yahr, 1986; D’Angio, Serano, Rivey & Scatton, 1987). T h e reason for these discrepancies may depend on the type of stressors used and the nature of the elicited behavioural or associated neuroendocrine response. A resolution of this controversy may depend upon identifying specific inputs


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to the dopamine cells in the midbrain, from which the mesocortical, mesolimbic and mesostriatal projections arise, which may mediate different forms of non-specific (or specific) sensory stimulation. However, few double dissociations have been shown of the effects of different stressors on different components of the forebrain dopamine projections. It is therefore probably safer at present to assume that stressors may globally affect all dopamine projections, but that their precise effects depend upon their intensity and on the regulatory mechanisms for altering the balance between cortical and subcortical dopamine activity. IV. SENSORIMOTOR INTERPRETATIONS OF HYPOTHALAMIC AND DOPAMINERGIC LESIONS (I)

Sensorimotor test batteries and neglect

As part of a more detailed analysis of stimulus-bound aggression in cats, McDonnell & Flynn (1966) noted that one effect of hypothalamic stimulation was to increase the size of the peripheral receptive field on a cat’s muzzle within which tactile stimulation would induce mouth opening and biting reflexes. This led Marshall, Turner & Teitelbaum ( I 97 I ) to consider whether the motivational effects of hypothalamic lesions might be associated with changes in the animal’s sensitivity to multimodal sensory stimulation. They therefore developed a simple neurological test battery for rats in which they assessed the animals’ orientation to spatially localized visual, tactile and olfactory stimuli, and a variety of limb placing, grasping and withdrawal reflexes. Unilateral lesions of either the lateral hypothalamus, the amygdala or the nigrostriatal dopamine pathway induce profound impairments in responding to stimuli in contralateral space and in making precise reflexive movements with the contralateral limbs (Marshall & Teitelbaum, 1974; Marshall et a l . , 1974). Marshall and colleagues argued that the deficit in rats with unilateral lesions is not primarily sensory, since the animals still make non-lateralized responses to contralateral stimuli, such as vocalization to a pin prick, even though they do not orient towards or bite the eliciting stimulus as would an intact animal. Similarly, the deficit was not considered to be primarily motor since a lesioned animal would still use the contralateral limbs normally in automatic response sequences such as locomotion or grooming. Rather, they argued that the deficit should be considered ‘sensorimotor ’, i.e. involving the disorganization of a co-ordinated lateralized response to specific lateralized eliciting stimuli. The first direct attempt to test the sensorimotor hypothesis was made by Turner (1973) who used a conditioning paradigm to train separate groups of rats to make a lateralized head turn response to escape from an electrical shock applied to the hindpaw. Separate groups of rats were pretrained to make the response to either the same side or the opposite side of the body as the aversive stimulus. Lateral hypothalamic or amygdala lesions disrupted performance only in the condition where both the stimulus and the response were contralateral to the lesions, whereas the animals were quite capable of making an ipsilateral response to a contralateral stimulus (ruling out a pure contralateral sensory deficit) as well as of making a contralateral response to an ipsilateral stimulus (ruling out a pure contralateral motor impairment). Unfortunately, Turner’s original study did not directly assess the effects of dopaminergic manipulations, and this gap has only been investigated recently (see the

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studies by Carli, Evenden & Robbins, 1985, and Carli, Jones & Robbins, 1989, Section VI. I). By contrast, the more widespread use of neurological test batteries modelled on the ones developed by Marshall have been extensively used to replicate a neglect of contralateral stimuli following 6 - O H D A lesions in the substantia nigra, nigrostriatal pathway and neostriatal terminal areas (Ljungberg & Ungerstedt, 1976 ; Marshall, Berrios & Sawyer, 1980; Dunnett & Iversen, 19826; Lees, Kydd & Wright, 1985), although the exact nature of the underlying impairment is not resolved by such tests. (2)

Sensorimotor interpretations of eating and rotation dejicits

Interest has focused on the sensorimotor interpretation of nigrostriatal and lateral hypothalamic function because it appears to provide an explanation for a wide range of phenomena associated with manipulations in these systems. T h u s , in addition to the eating and drinking impairments that follow bilateral lesions, the animals show a bilateral neglect of salient external stimuli. I t might therefore appear plausible to interpret the more debilitating impairments in eating and drinking manifested by these animals in terms of a neglect of the internal stimuli arising from contractions in the stomach, taste receptors in the mouth, or gluco- and osmoreceptors in the hypothalamus, which are associated with hunger and thirst. T h e lesioned animal then does not eat and drink in response to tissue needs not because it is not ‘hungry’ or ‘thirsty’ but because it neglects the signals associated with those needs. ,4 similar reasoning has been applied to the very different phenomenon of rotation. An activated animal will approach relevant stimuli in its external environment. Following a unilateral lesion it neglects the contralateral half of space and so turns ipsilateral to the lesion by virtue of approach only to external stimuli on the ipsilateral side. However, considerable caution is necessary. At the experimental level, a dissociation has been observed between changes in rotation, sensorimotor responses and regulatory behaviours in response to implantation of transplants of dopaminergic neurons in animals with nigrostriatal lesions. T h u s , it has been found to be possible to replace damaged dopamine systems by transplantation of embryonic dopamine neurons to the lesioned brain in rats (Bjorklund & Stenevi, 1979), and such grafts are capable of alleviating both rotation and sensorimotor deficits of the host animals (Dunnett, Bjorklund, Stenevi & Iversen, 1981a-c). However, it Lvas found that the grafts had to be placed in the dorsal neostriatum to alleviate rotation, but into the ventrolateral neostriatum to alleviate sensorimotor neglect. Moreover, neither graft placement protected the rats from profound aphagia and adipsia following bilateral lesions. T h i s comparison of effective graft placements indicated a three-way dissociation between the different classes of behavioural deficit, which suggests that neither rotation in rats with unilateral lesions nor regulatory deficits in rats with bilateral lesions is likely to be a direct consequence of a more general sensorimotor impairment (Dunnett, Bjorklund, Stenevi & Iversen, 19816). At a more conceptual level, although labelling a deficit ‘ sensorimotor ’ can provide a useful shorthand description of the results, this provides little insight into the nature of the underlying impairment or the functional contribution of the forebrain dopamine system to response selection and control. All aspects of central processing are encompassed by the description, excluding by definition only primary input and output


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mechanisms. Thus, for example, a failure to eat in the absence of functional dopaminergic activation of the forebrain might be attributable to a failure to detect the relevant stimuli, an attentional failure involving neglect of those stimuli, or an impairment in the selection, initiation or organization of a relevant response to those stimuli - all of which are encompassed within a sensorimotor description. Instead, it is necessary to refine the level of analysis to identify more precisely the nature of the deficit underlying the diverse range of symptoms associated with dopaminergic depletion. V. COGNITIVE EFFECTS O F NEOSTRIATAL AND DOPAMINERGIC LESIONS

Dopamine concentrations reach their highest level in the neostriatum of the mammalian brain. This is an undifferentiated nucleus in rodents but is subdivided by the internal capsule into caudate nucleus and putamen in carnivores and primates. The neostriatum receives a dense, topographically organized input from the whole neocortical mantle, and has been associated with cognitive as well as motor functions. Thus, for example, Rosvold and colleagues (Rosvold, Mishkin & Szwarcbart, 1958; Rosvold & Szwarcbart, 1964) found that lesions in the caudate nucleus of monkeys produced deficits on tasks classically associated with the prefrontal lobes, such as delayed response and delayed spatial alternation. The first studies to consider whether the dense dopaminergic innervation of the neostriatum contributes to the cognitive capacities of the animal employed bilateral 6OHDA lesions of the ascending forebrain dopamine pathways in rats. Because of the animals’ akinesia and motivational impairments, standard appetitive operant or mazelearning tasks are not appropriate, but the animals will still respond to aversive stimuli. Thus, Ranje & Ungerstedt (1977) found that rats with bilateral lesions could still swim vigorously to escape from water in a submerged T-maze. Although their animals were able to retain spatial and brightness discriminations that had been learned preoperatively, they were unable to learn such discriminations postoperatively. By contrast, when rats are trained to locate an escape platform in the Morris water maze, Hagan, Alpert, Morris & Iversen (1983) found no learning deficits other than increased escape latencies, which could equally be attributable to a moderate motor impairment. However, in this study, all animals with substantial sensorimotor impairments (and correspondingly extensive dopamine depletions) were excluded, whereas it is precisely such animals that appear unable to learn the location of the escape platform in this task (Whishaw & Dunnett, I 985). Nevertheless, although motor impairments cannot account for all such learning deficits, since even animals with extensive lesions swim efficiently, it is not clear that the learning deficits are truly cognitive in nature. For example, the selection of appropriate strategies in swim maze tasks involves use of available distal stimuli, so that deficits in task performance may be related to the phenomena of sensorimotor neglect (Whishaw & Dunnett, I 985). Moreover, the slowed swimming speed produced by caudate DA depletions could be reversed by having the rats swim in cold water (Selden, Cole, Everitt & Robbins, 1990), suggesting an activational deficit reminiscent of so-called ‘ paradoxical kinesia ’ in Parkinson’s disease (Schawb, 1972). An alternative approach is to take advantage of the topographic organization of corticostriatal projection and use focal striatal lesions, following which no generalized

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motor or motivational impairments are detectable. Divac, Rosvold & Szwarcbart ( I 967) provided the first clear evidence in monkeys that the caudate nucleus is itself topographically organized by function. They based their experimental design on evaluating monkeys with circumscribed caudate lesions on tasks that were known to be sensitive to lesions in discrete cortical areas, and found : ( a ) Lesions in the anteromedial caudate nucleus, which receives inputs from the dorsolateral prefrontal cortex, disrupted monkeys’ performance of delayed spatial alternation, a task sensitive to dorsolateral prefrontal ablation. (b) Lesions in the ventrolateral caudate, which receives inputs from the orbital prefrontal cortex, disrupted monkeys’ performance of an object reLrersa1 task that is sensitive to orbital prefrontal ablation. (c) Lesions in the tail of the caudate nucleus, which receives inputs from the inferotemporal cortex, disrupted monkeys’ performance on a visual discrimination task that is sensitive to dorsolateral prefrontal ablation. Thus, lesions in the neostriatal zones receiving projections from each of several discrete areas of association cortex were each found to produce deficits in the same cognitive tasks as are sensitive to lesions in the respective neocortical areas. These primate studies employed electrolytic lesions, which are subject to the criticism that such traditional non-specific lesion techniques can cause extensive damage to the internal capsule fibres carrying afferent and efferent connexions to the neocortex, independently of the caudate nucleus itself (Laursen, 1963). In order to overcome this problem, striatal organization has been investigated more recently by using cell-specific neurotoxins, such as kainic acid or ibotenic acid, in rodents (McGeer & McGeer, 1981). In rats, the medial prefrontal cortex projects to the anteromedial zone of the neostriatum, whereas the orbital prefrontal cortex projects to the ventrolateral zone (Beckstead, 1979). In direct parallel with the study of Divac and colleagues, lesions in the anteromedial neostriatum disrupt rats’ performance on classical medial prefrontal tasks, such as delayed spatial alternation or reversal learning, whether made by kainic acid to destroy intrinsic striatal neurons or 6-OHDA to deprive the neostriatum of its dopaminergic innervation (Divac, Markowitsch & Pritzel, 1978; Dunnett & Iversen, 1979, 1981; Simon, 1981). Similarly, kainic acid and 6-OHDA lesions of ventrolateral neostriatum disrupt performance on tasks sensitive to orbital prefrontal lesions, such as D R L performance or runway extinction (Dunnett & Iversen, 1981, 1982a). More recent studies have included ventral striatal sites (nucleus accumbens) along with other neostriatal subregions. Thus, Reading, Dunnett & Robbins (1991) found that the acquisition of a conditional yisuospatial task is sensitiL-eto excitotoxic lesions of both the lateral striatum and nucleus accumbens, but not the medial striatum, effects which are mimicked by dopamine depletion of the entire dorsal, but not ventral, striatum (Robbins, Giardini, Jones, Reading & Sahakian, I 990). Moreover, whereas dorsal striatal lesions induce a generalized disruption of spatial delayed matching to sample performance, ventral striatal lesions induce more selective delay-dependent deficits in short-term memory (Dunnett, I 990 ; Reading & Dunnett, r991), which are reproduced by dopaminergic deafferentation of the same area (P. 3. Reading & S. B. Dunnett, unpublished observations). Thus, performance on such tasks is clearly dependent on the integrity both of intrinsic neurones and of their dopaminergic innervation within discrete striatal zones. Oberg & Divac (1979) have argued from such data that the primary function of the striatum is in essence cognitive, i.e. involved in the processing of associatiye, mnemonic

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and complex perceptual information. However, it is difficult to resolve from the lesion data the nature of the processing intrinsic to the striatum from that taking place in the cortex, the outflow of which is disrupted by the striatal manipulation. It is nevertheless the case that the neostriatum, as an essential component of multiple association cortical systems, is necessary for intact cognitive performance, and that the nigrostriatal dopamine input provides an essential regulatory control over the striatal outflow from such cortical systems. VI. ROLE OF DOPAMINERGIC SYSTEhlS I N RESPONSE SELECTION

( I ) Response initiation following nigrostriatal lesions

T h e debate about the nature of processing taking place within the neostriatum has been highlighted by the debate between Oberg & Divac (1979, 1981) arguing the cognitive case on the one hand, and Marsden (1980, 1982, 1984) refining traditional views in terms of motor control on the other. Marsden reviewed studies of the effects of dopamine deficiency in Parkinson’s disease, and found little evidence for primary cognitive or sensory impairments in other than a small proportion of patients. Rather, he argued that the overwhelming impairment is motor, and in particular a poverty in spatial and temporal aspects of the planning and control of action. These clinical observations have recently been confirmed in several detailed experimental studies of movement in parkinsonian patients. Thus, Sheridan, Flowers & Hurrell (1987) found impairments in initiating a simple lever movement, even in conditions where minimal motor programming is required and a greater deficit when the lever movement involved aiming at a target. Benecke, Rothwell, Dick, Day & Marsden (1986) similarly found significant slowing in patients making simple selfpaced ‘flex’, ‘squeeze’ and ‘cut’ hand movements, but much greater deficits when the movements required simultaneous coordination (Benecke et al., I 986) or sequential ordering (Benecke, Rothwell, Dick, Day & Marsden, 1987). In considering precise motor control in animals, one line of research has involved a variety of paw reaching tasks in rats, modelled on those originally designed by Peterson (1934) and Castro (1972) for the study of motor cortex function. Both excitotoxic lesions of the intrinsic neurons of the neostriatum made with ibotenic acid and 6OHDA lesions of the dopaminergic afferents to the same areas of neostriatum disrupt rats’ abilities to use the contralateral limb to lever press or to reach, grasp, manipulate and retrieve food pellets from tubes or food wells (Siegfried & Bures, 1980; UguruOkorie & Arbuthnott, 1981; Evenden & Robbins, 1984; Sabol, Neill, Wages, Church & Justice, 1985; Whishaw, O’Connor & Dunnett, 1986; Pisa, 1988; Montoya, Astell & Dunnett, I 990). The most common effect observed in these studies was a switch in paw preference to sole use of the ipsilateral limb for responding. However, the capacity of the contralateral limb can be assessed if use of the ipsilateral limb is restricted by local anaesthetic, a bracelet, or the configuration of the test apparatus. In these circumstances, the animals attempt to use the contralateral paw but with a marked reduction in accuracy and manipulative precision (Whishaw et al., 1986; Montoya et al., 1990). These effects of unilateral dopaminergic lesions are entirely consistent with previous suggestions of spontaneous dopaminergic asymmetries mediating paw preferences in the intact animal (Glick & Jerussi, 1974; Glick & Ross, 1981). In closer parallel with the clinical experiments, studies involving precise timing of 20

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movement in experimental animals with dopamine-depleting lesions are sparse. In one primate study, unilateral 6-OHDA lesions of the substantia nigra revealed impairments in both initiation time and movement time but not in response accuracy in baboons trained to make a reaching movement Lvith the contralateral hand (Viallet, Trouche & Nieoullon, 1986). These observations have been confirmed in a small New World primate, the marmoset, in which similar unilateral nigrostriatal lesions induced marked contralateral impairments in initiating and the time taken to complete a variety of reaching and manipulative tasks using the contralateral hand (Annett, Rogers, Hernandez & Dunnett, 1992). In another series of studies, using rats Carli e t al. (1985, 1989) employed an appetitive visual discrimination task in a counterbalanced version of the Turner paradigm (see Section 1V.r). Rats were trained to poke their noses into a central hole, and then to respond to light flashes on the right or left side by making a nose poke into one of two response holes situated on either side of the central hole. One group of rats was trained to nose poke in the hole on the same side as the stimulus light, whereas the other group was trained always to respond in the hole on the opposite side to the stimulus light. Then all rats were given a unilateral 6-OHDA lesion of the nigrostriatal terminals in the neostriatum. Both groups of rats showed an increased number of responses to the side ipsilateral to the lesion, irrespective of the side of the stimulus light. More specifically, as all response holes were monitored by photocell beams, the animals’ response latencies were subdivided into an initiation time (the time taken to withdraw the nose from the central hole), and a movement time (the time taken to complete the movement and register a nose poke in the lateral response holes). Remarkably, the dopaminergic lesions slowed the initiation of a movement that was to be made in the contralateral direction, even though the initiation component of the movement was a non-lateralized withdrawal of the nose from the hole. By contrast, the time taken actually to execute the lateralized movements was unaffected by the lesions. This result adds considerable precision to the relatively vague notion of ‘ sensorimotor ’ impairment, and indicates that the unilateral dopaminergic lesions produce a specific deficit in the initiation of a goal-directed movement, rather than in its execution. Amalric & Koob ( I 987) reached a similar conclusion from the effects of 6-OHDA lesions on rats’ performance in a reaction time task. Rats were trained to hold down a lever and then release it as quickly as possible after presentation of a light stimulus. Dopamine receptor blockade by peripheral injection of a-flupenthixol or 6-OHDA lesions of neostriatum both impaired the rats’ speed of responding, whereas nucleus accumbens lesions had no effect. T h e effect of the lesion in this task is thus explicitly to impair the initiation of a conditioned movement to a sensory cue. In a quite different task, Dunnett & Bjorklund (1983) trained rats to rotate (in the absence of any lesion-induced asymmetry) for water reward. T h e rats were then given unilateral 6-OHDA lesions of the nigrostriatal bundle on either the ipsilateral or the contralateral side to the direction of training. Ipsilateral lesions had no effect on conditioned turning, whereas contralateral lesions markedly disrupted the animals’ ability to turn in the reinforced direction. These latter animals appeared to ha1.e difficulty initiating the contralateral movement, and instead tended to hover at the choice point until a turn was made, most often in the non-reinforced ipsilateral direction. However, on the occasions where a contralateral turn was initiated, the


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movement was then completed with normal morphology and speed. So again the lesions appeared to induce a deficit in the initiation rather than in the execution of a goal-directed action. These studies do not, of course, identify which of the several processes that contribute to response initiation is most affected by striatal DA depletion. However, a recent study by Brown & Robbins ( 1 9 9 1 )has shown that profound unilateral striatal depletion impairs the ability of rats to initiate responses in both simple and choice reaction time tasks to an equivalent degree. The impairment also depended upon the delay between the initiation of the trial and the onset of the imperative signal to respond. This pattern of results is compatible with an interpretation in terms of an impairment in processes of motor readiness rather than in programming specific responses. (2)

Response switching and incentive motivation following ventral striatal lesions

Although amphetamine induces perseveration and stereotypy at high doses, the behavioural competition model advanced earlier suggests that this drug also increases the tendency to switch between different responses at lower doses. Some evidence for this has been obtained in a task in which rats have to shift between two levers in an operant setting while responding for food reward (Evenden & Robbins, 1983). The ventral striatal dopamine projection may play an important role in behavioural switching, because of its implication in locomotor activity in the rat, particularly following the response to amphetamine (Kelly et al. 1975). Increasing levels of locomotion enable the rat to move its body to sample different salient distal cues. These distal stimuli will include important goals or rewards, contact with which is essential for the survival of the animal. Such approach responses to goals and other forms of appetitive behaviour anticipating contact with reward are often considered to be the product of incentive-motivational processes and activity in the mesolimbic dopamine system has been equated with such an incentive-motivational function (see Fibiger & Phillips, 1986). Thus, processes of behavioural switching can be seen to enable the animal to share its time efficiently between different sources of reward. A similar function may underlie the excessive head-checking movements induced by infusions of the drug into the nucleus accumbens of marmosets (Annett, Ridley, Gamble & Baker, 1983). These examples of increased activity following amphetamine may be the abnormal expression of more fundamental changes in attention or incentive-motivational processes. Certainly, it appears that, even in the rat, mesolimbic dopamine effects more aspects of the response to amphetamine than can easily be ascribed to enhanced locomotor activity per se. For example, dopamine depletion from the nucleus accumbens blocks the rate-dependent effects of amphetamine on operant behaviour (Robbins, Roberts & Koob, 1983), its disruptive effects in attentional tasks and on scheduleinduced polydipsia (Robbins et a l . , 1983; Robbins, Evenden, Ksir, Reading, Wood & Carli, 1986), its potentiation of the effects of stimuli associated with reward (or conditioned reinforcers; Taylor and Robbins, 1986), its capacity to act as a selfadministered reinforcer (Lyness, Friedel & Moore, 1979), and as an appetitive unconditioned stimulus in place preference conditioning (Spryaki, Fibiger & Phillips, 1982). 20-2

S.B. DUNNETT AND T. u’. ROBBINS By contrast, it has proved more difficult to demonstrate robust effects of mesolimbic dopamine depletion on normal (as opposed to drug-induced) behaviour. Mesolimbic dopamine depletion does not reliably affect spontaneous locomotor activity, but does reduce activity elicited by the presence of food in hungry rats (Koob, Riley, Smith & Robbins, 1978). T h i s study found that 6-OHDA lesions of the nucleus accumbens did not reduce feeding; indeed, in restricted feeding situations it was prolonged and more food was eaten when compared with sham-operated controls. T h e increased feeding was accompanied by reductions in food-associated drinking. I t was also observed that the animals were less able to switch between different water tubes when deprived of water, although this effect was relatively transient (Robbins & Koob, 1980). A later study (Evenden & Carli, 1985) found no effect of accumbens lesions on switching between different food containers in an open field setting, although this study confirmed the long-lasting nature of the enhanced feeding response in the lesioned animals. One of the most reliable effects of mesolimbic dopamine depletion is to prevent the acquisition of schedule-induced polydipsia (SJP), in which the periodic presentation of small food pellets to food-deprived animals results in an excess drinking that cannot be explained in terms of physiological fluid deficits or superstitious behaviour (Robbins & Koob, 1980; Wallace, Singer, Finlay & Gibson, 1983). T h i s effect has also been shown for other forms of schedule-induced behaviour such as wheel running (Wallace et al., 1983). T h e reduction in S I P does not occur so reliably following mesostriatal dopamine depletion ; the volume ingested may decline, but licking may actually increase, indicating a possible deficit in motor efficiency (Mittleman, Whishaw, Jones, Koch & Robbins, 1990).These observations of a form of ‘displacement activity’ support the suggestion that the mesolimbic dopamine depletion is producing some kind of deficit in response switching, possibly linked to impaired incentive motivation. There is some additional evidence of behavioural rigidity in rats with ventral striatal lesions that cannot easily be ascribed to motor response-related deficits. For example, rats with mesolimbic dopamine depletion exhibit reduced alternation in a T maze and increased resistance to extinction (Taghzouti, Simon & L e Moal, 1985; Robbins et al., 1990). T h e y are also slow to adapt to alterations in schedules of reinforcement, even when the adaptation entails response perseveration (Evenden, I 983). T h i s enhanced rigidity is suggestive of an alteration in attentional processes following ventral striatal dopamine depletion. However, mesolimbic dopamine depletion does not have profound effects on other tasks that have been used to measure attention in the rat. For example, Robbins et al. (1986) found only transient effects in a discrimination task which measured the animal’s ability to switch attention between stimulus lights of different durations. Similarly, responding in a serial 5-choice visual discrimination task was slowed, errors of omission were increased for several sessions, but accuracy (as measured by errors of commission) was not significantly altered following mesolimbic 6-OHDA lesions of the mesolimbic dopamine system (Cole & Robbins, 1989). These effects contrast with those produced by damage to other ascending monoaminergic or cholinergic systems which can affect measures of accuracy without affecting the speed or general tendency to respond (Carli et al., 1983; Robbins & Everitt, 1987; Robbins et al., 19896). T h u s , if ventral striatal lesions do affect attentional processes, we suggest that this is at the level of response selection rather than of stimulus input.


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If processes of response selection are impaired by ventral striatal lesions, then it might be expected that the conditional visuospatial discrimination tasks described in Section V would also be susceptible in some way to ventral striatal damage. However, 6-OHDA lesions of the ventral striatum did not produce any major effect on either acquisition or performance of the frequency discrimination task, whereas both indices were seriously affected by lesions of the caudate-putamen (Robbins et al., 1990). These results would suggest either that the mesolimbic dopamine system is not necessary to sustain response selection in the context of complex discrimination tasks or that the system is extremely plastic in response to 6-OHDA-induced damage. Nevertheless, by contrast with dopaminergic lesions, excitotoxic lesions of the ventral striatum are effective in impairing both acquisition and performance on similar discrimination tasks (Reading et al., 1990), suggesting that the ventral striatum itself does play some role in response selection processes, whether or not it is critically dependent upon its dopamine inputs. In future studies, it will be important to delineate the relative roles of the dorsal and ventral striatum in the various aspects of response selection. One possibility is suggested by other results from the two experiments just considered : both 6-OHDAinduced and excitotoxic lesions of the ventral striatum dramatically enhanced the animals’ resistance to extinction (Robbins et al., 19896; Reading et al., 1992). Thus, it is possible that the ventral striatum is implicated in the behavioural plasticity required in the face of changing reinforcement contingencies. A further implication is that this enhanced rigidity of behaviour occurs because the dorsal striatum mediates learned stimulus-response habits (such as conditional discrimination ; Robbins, Cador, Taylor & Everitt, 1989a; White, 1989), and that it is normally subject to inhibitory control from the ventral striatum. Interactions between the dorsal and ventral striatum are discussed further below. VII. AN INTEGRATED ROLE FOR FOREBRAIN DOPAMINE SYSTEMS

Although ventral and dorsal striatal dopamine systems may be implicated in different functions, the differences may well be determined by the other inputs to these regions. For example, the ventral striatum receives a strong allocortical input from the prefrontal cortex and amygdala, which may be important for the convergence of information about reward, whereas the neocortical inputs of the dorsal striatum may be implicated in cognitive and response-related functions, such as visuospatial processing and attention to action. This can account, for example, for the different effects of ventral and dorsal striatal dopamine depletion upon consummatory responding on the one hand and ‘preparatory ’ (or incentive-linked) behaviour on the other. The hypothesis of an involvement of the ventral striatum in reward-related processes is not new (e.g. Phillips & Fibiger, 1973), but the precise mechanism by which the activating effects of amphetamine or related stimulants can provide reinforcing effects has yet to be specified in detail. On the other hand, the aphagia and adipsia that are seen after nigrostriatal dopaminergic degeneration may well result from a disruption of sensorimotor co-ordination and sequencing of appropriate goal-directed actions. The characterization of lesion effects in terms of a separation into consummatory and incentive-linked behaviours reflects the same dichotomy that is observed after challenge with amphetamine : the predominantly oro-facial stereotypies are reduced after

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dopaminergic depletion of the more dorsal caudate-putamen, whereas the locomotor activity as a prominent component of incentive motivation is more susceptible to dopamine depletion of ventral striatal areas. Such a separation of forebrain dopamine terminal systems into domains with distinct effects on different behavioural processes does not, of course, imply that only one system would be active in a given behavioural situation. For most situations, and in particular those involving complex behavioural tasks, quite the opposite would occur. I n particular, the net impact of combined lesions of dorsal and ventral striatum on performance would be expected to be far greater than the effect of lesions restricted to one or other terminal domain. Koob, Simon, Herman & L e Moal ( I 984) have reported precisely such an effect of combined dorsal and ventral striatal lesions on active avoidance in the rat. However, this does not imply a ‘mass action’ effect of the dopaminergic depletion on a single function, but rather that several behavioural processes contribute to successful active avoidance, including responding to the aversive condition stimuli and preparing the appropriate locomotor response. T h e important question to resolve is how the functions of these several forebrain systems are integrated and co-ordinated to produce a coherent behavioural output. T h e activity of dorsal and ventral striatum may be co-ordinated, in one sense, as a general response to activating stimuli which leads to behavioural activation. Such global motivational activation serves to prime and facilitate consummatory behaviour and behaviour instrumental in gaining access to rewards. T h i s is achieved by a mechanism of amplification of the response of the distinct striatal regions to their dominant inputs. It is apparent that such global activation, if excessive as in the case of amphetamine overdose, leads ultimately to a disintegration of behaviour which is the antithesis of coordination. However, some responses at lower doses, such as rotation in animals with unilateral lesions, have been shown to depend on the co-ordination of two different types of response d the head turn and postural deviation mediated by the caudateputamen, and the whole-body movement mediated by the nucleus accumbens (see Section 11.3). Somehow, these two responses are integrated to provide a co-ordinated although asymmetrical rotational response by the animal. Presumably, the striatal outflow is modulated by mechanisms which produce a patterned outflow to the effectors so that these different aspects of the response are performed in an appropriately ordered sequence. T h i s type of co-ordinated, although nevertheless stereotyped, responding is also observed in more dramatic form when animals treated with amphetamine adopt intricate perseverative routes for locomotion (Sahakian & Robbins, I 975 ; Segal, 1975). It is evident at this stage of stereotypy that experimental and environmental factors are still exerting a degree of control over the stereotyped output. T h e issue of co-ordination is not easily resolved by the parallel nature of striatal outflows, as recently emphasized by DeLong and colleagues (DeLong & Georgopoulos, 1981 ; Alexander, Delong & Strick, 1986). Presumably, considerable ‘crosstalk’ is required between these apparently specialized lines of communication. It is also evident that co-ordination has to occur between the different dopamine terminal regions at a much more localized and precise level than a simple gross distinction between the nucleus accumbens and dorsal striatum of the rat. Even in that species, it is apparent that stereotypies contribute more to the induction of amphetamine anorexia than competing locomotor activity, as shown by the greater effects of dopamine depletion


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from the caudate-putamen than from the nucleus accumbens upon this phenomenon (Koob et al., 1978; Joyce & Iversen, 1984). These observations suggest that response switching may be an emergent function affected by dopamine activity throughout the striatum, as originally suggested by the Lyon-Robbins hypothesis, and by the experimental results of Cools, Jasper, Kolasiewicz, Sontag & Wolfarth (1983). Recent evidence suggests that the concept of lack of co-ordination in dopamine release in diverse forebrain regions may also have implications for cognitive functions modulated by dopamine. Gotham, Brown & Marsden (1986) have reported that patients with Parkinson’s disease exhibit greater deficits in tasks sensitive to frontal lobe damage when under L-DOPA medication than when off the drug. They speculate that this could result from an ‘overdose’ of L-DOPA being administered to the caudate nucleus in such patients, as a side effect of attempting to replenish the more profoundly depleted putamen. Their results resemble the disruption of cognitive behaviour produced by amphetamine in animals (Kesner, Bierley & Pebbles, 1981). In normal circumstances, we assume that dopaminergic activity is regulated. This takes place not in the manner of a static feedback control system, but in a more dynamic way dependent upon environmental contingencies. There are three main types of influence that can be listed. ( a ) The striatal feedback projection to the dopamine cell bodies of origin. These are not in themselves sufficient to achieve a co-ordinated regulation in activity. This may depend upon the pattern of activity set up within different sub-regions of the striatum by its allocortical and neocortical inputs. Thus, we can conceive of dopaminergic activity waxing and waning in different sub-regions to amplify processing there, as a function of the profile of cortical inputs. This would be a highly dynamic form of regulation, sufficient to achieve a co-ordination of motor and cognitive output. ( b ) The nucleus accumbens itself has connexions with the substantia nigra pars compacta, by which it can exert a collateral regulatory influence (Nauta, Smith, Faull & Domesick, 1978; Nauta & Domesick, 1984). This might provide either inhibitory interruption or gain amplification of nigrostriatal activity. The reciprocal type of interaction is not known to be anatomically present. Although this form of regulation appears potentially important, there is as yet little convincing evidence that this is the case. (c) The frontal cortical dopamine projections may have an important role in the regulation of subcortical dopamine activity (Pycock, Carter & Kerwin, I 980; Pycock, Kerwin & Carter, 1980; Rosin, Deutsch & Roth, 1987; Tassin, HervC, Verzina, Trovero, Blanc & Glowinski, 1991).For example, some of the reported effects of frontal cortex dopamine depletion on locomotor activity may result from a dysregulation of subcortical dopamine function (Carter & Pycock, 1980). It is possible that the apparent susceptibility of frontal cortex dopamine systems to stressful stimuli reflects in part a ‘ feed-forward ’ function to dampen the effects on those dopamine-dependent regions concerned with the implementation of appropriate action to that stressor. This action could be expressed in terms of both the initiation of specific action and also the cognitive functions we have seen to be mediated by striatal mechanisms. A possible functional correlate of this action of mesocortical dopamine may be a form of ‘ coping response’ which regulates and thus limits the effects of a stressor. Other converging lines of biochemical and electrophysiological evidence suggest that

S. B. DUNNETT AND

‘r.W. ROBBINS

the central dopamine systems also exhibit a degree of self-regulation at several levels, including ‘ autoinhibition ’ via dendro-dendritic contacts in the substantia nigra (Groves & Tepper, 1983; Kuczenski, 1983), and influences both at presynaptic receptors (Carlsson, 1975, 1987), and via post-synaptic coupling of D, and D, receptors in the neostriatum (see Section 11.2). T h e relationship between these forms of regulation and those we have described is currently unknown, but such processes almost certainly contribute to the neuronal mechanisms by which behavioural coordination is achieved. VIII. ACKNOWLEDGEIIEKTS O u r studies have been supported predominantly by grants from the Medical Research Council and the W’ellcome T r u s t .

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Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

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Hyperactivity following intradentate injection of colchicine: a role for dopamine systems in the nucleus accumbens.

The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia.

The expanding role of dopamine.

Second messenger systems: functional role in cerebrovascular smooth muscle regulation.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 2.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 1.

A new dopamine agonist in dopamine deprived systems: FCE 23884.

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. I. Behavioral and biochemical studies.

The role of dopamine in motor flexibility.

The role of dopamine in mood disorders.

Role of the mesostriatal dopamine pathway.

Dopamine-mediated changes in central nervous system neurotensin systems: a role for NMDA receptors.

Dopamine Modulates the Functional Organization of the Orbitofrontal Cortex.

Interactions between central monoaminergic systems: dopamine-serotonin.

Peptide hormones and central dopamine neuron systems.

Dopamine signaling in food addiction: role of dopamine D2 receptors.

The physiological relevance of functional selectivity in dopamine signalling.

The role of the systems analyst.

Functional development of dopamine receptors in the rat forebrain.

Mesotelencephalic dopamine system and reproductive behavior in the female rat: effects of ventral tegmental 6-hydroxydopamine lesions on maternal and sexual responsiveness.

Cross-hemispheric dopamine projections have functional significance.

Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease.