The neuropsychological basis of addictive behaviour

Transcription

1 Brain Research Reviews 36 (2001) locate/ bres Review The neuropsychological basis of addictive behaviour * Barry J. Everitt, Anthony Dickinson, Trevor W. Robbins Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK Abstract The argument advanced in this review is that drug addiction can be understood in terms of normal learning and memory systems of the brain which, through the actions of chronically self-administered drugs, are pathologically subverted, thereby leading to the establishment of compulsive drug-seeking habits, strengthened by the motivational impact of drug-associated stimuli and occurring at the expense of other sources of reinforcement. We review data from our studies that have utilized procedures which reveal the various influences of pavlovian stimuli on goal-directed behaviour, namely discriminated approach, pavlovian-to-instrumental transfer and conditioned reinforcement, in order to demonstrate their overlapping and also unique neural bases. These fundamental studies are also reviewed in the context of the neural and psychological mechanisms underlying drug-seeking behaviour that is under the control of drug-associated environmental stimuli. The ways in which such drug-seeking behaviour becomes compulsive and habitual, as well as the propensity for relapse to drug-seeking even after long periods of relapse, are discussed in terms of the aberrant learning set in train by the effects of self-administered drugs on plastic processes in limbic cortical ventral striatal systems Elsevier Science B.V. All rights reserved. Theme: Neural basis of behaviour Topic: Drugs of abuse: cocaine; Drugs of abuse: opioids and others Keywords: Addiction; Reward; Conditioning; Cocaine; Heroin; Actions; Habit; Drug-seeking Contents 1. Introduction Appetitive pavlovian conditioning: autoshaping Pavlovian-to-instrumental transfer Conditioned reinforcement Synthesis Acknowledgements References Introduction that develop with chronic drug administration [62 64]. But understanding the precise relevance of these neuroadapta- Drug addiction places a significant burden on society tions to the clinical reality of drug addiction in humans through its impact on health, social cohesion, crime and remains a major challenge. comorbidity with neuropsychiatric disorders. Major ad- Many drugs of abuse, including amphetamine, cocaine, vances in genetics, molecular and cell biology have led to heroin, nicotine, cannabis and alcohol, while having very the identification and cloning of many of the primary different primary molecular targets, all have the common targets of addictive drugs and revealed neuroadaptations action of increasing dopamine (DA) transmission in the nucleus accumbens (NAcb), perhaps especially in its shell *Corresponding author. Tel.: ; fax: subregion [5,22,77,112]. This commonality of action has 564. led to the widely held view that the mesolimbic DA system address: bje10@cus.cam.ac.uk (B.J. Everitt). has a general role in the reinforcing effects of drugs, / 01/ $ see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S (01)

2 130 B.J. Everitt et al. / Brain Research Reviews 36 (2001) perhaps stemming from a more general role in mediating it occurs prior to drug infusion. However, it does depend aspects of natural reward [21,121,122]. Molecular neuro- upon the contingent presentation of cocaine- or heroinadaptations induced by chronic administration of cocaine, associated cues, since if they are not presented, then heroin, nicotine and alcohol have been shown to occur drug-seeking is markedly reduced and only recovers when downstream of DA receptors in the NAcb and elsewhere the cues are reintroduced [1,2]. This procedure not only [65], encouraging a view of drug addiction as gradual brain provides an opportunity to study the neural basis of such adaptations to chronic drug exposure, possibly triggered by cue-controlled drug-seeking, but also provides a means of a drive to homeostasis, i.e. the regulation of activity of assessing potential treatments that will diminish cue-conbrain systems affected by self-administered drugs within trolled drug-seeking (and relapse). The basolateral certain defined limits [49,50]. These neuroadaptations are amygdala (BLA) is a critical structure, since animals with the product of both decremental (tolerance/ withdrawal) lesions of the BLA cannot acquire a second-order schedule and incremental (sensitization) pharmacological effects. of cocaine-seeking [116]. Rats with lesions of the anterior Sensitization has acquired a recent prominence, espe- cingulate cortex (Ant Cing) and also medial prefrontal cially as conceptualized in the Incentive Sensitization cortex show persistent high levels of responding for Theory, which attributes the development of addiction to cocaine, but which is no longer under the control of the progressive establishment of compulsive drug want- contingent presentation of the cocaine-associated cue ing through up-regulation of the mesolimbic DA system [115]. Interestingly, the amygdala and Ant Cing have been [7,88,89]. By contrast, avoidance of the dysphoria and consistently shown to be activated in functional imaging anhedonia that follows withdrawal from many drugs studies of cocaine and heroin addicts when they are underlies another, compelling view that sees addiction as exposed to drug cues that elicit craving [15,35,98]. resulting from opponent motivational processes But the second-order schedule, by modelling the com- [48,103,118]. Whilst there have been recent and impressive plex contingencies of natural drug-seeking, engages a attempts to reconcile these viewpoints [49,50], it is likely number of different learning and motivational processes. that further precision is required in specifying the psycho- We have been concerned to understand the contribution of logical processes determining human drug addiction [108] each of these processes to drug-seeking, as well as their and in the interpretation of the molecular and neurochemi- neural basis. In order to do so, we have developed different cal correlates of chronic drug administration. behavioural procedures, each of which focuses more The case for modelling addictive processes in animals directly on a component process. We distinguish between has been strongly made [33,62,84]. Apart from their pavlovian processes sensitive to the contingency between greater neurobiological accessibility, a key point is that stimuli (S) and reinforcers or outcomes (O) and instrumenanimals can be studied from the drug naıve state through tal processes sensitive to the contingencies between acdependence, whereas clinical studies begin with an ad- tions or responses (R) and outcomes [24]. In order to study dicted individual who is usually seeking help to maintain the instrumental processes in more detail, we developed a abstinence. Among the processes to be further character- seeking taking chain schedule [68] in which an animal ized and understood are those underlying: (i) vulnerability; performs a drug-seeking response in the initial link of the (ii) the maintenance of drug-taking/ seeking behaviour, chain which then gives access to a drug-taking response in which might be viewed as a dynamic product of the the second link, performance of which delivers the drug. gradual strengthening or consolidation of behaviour By varying the dose and time-out period between succesarising from the reinforcing action of drugs, supplemented sive cycles of the chain, we demonstrated that cocaineby a recurrent shaping of drug-related memories; (iii) the seeking is governed by an interaction between reineventual progression of addiction to a form of habit-based forcement, regulatory, and activational processes [68]. learning through which voluntary control over drug use is Moreover, after a limited experience with the drug, lost [66,84]; (iv) the propensity for relapse of drug-seek- cocaine-seeking was shown to be a goal-directed action in ing/ taking, which often occurs after protracted abstinence. that its performance was sensitive to devaluation of the In our recent research, we have placed special emphasis drug-taking link [67]. This devaluation effect demonstrates on the fact that drug abusers have to forage for their drugs that, under the conditions we have studied so far, cocainein a real world in which they are not freely available seeking is mediated by knowledge of the contingency [28,84,116]. We have established a general model of drug- between the seeking response and its outcome, in this case seeking and taking in which this behaviour is sensitive not access to the drug-taking link. This R O process can be only to the contingency between instrumental behaviour contrasted with the second, S R instrumental process in and drug administration, but also to the presence of drug- which seeking behaviour is a simple response habit associated stimuli which have a powerful effect on per- triggered by environmental and drug-associated stimuli. In formance [1,2]. In this procedure, rats respond for pro- the case of drug-seeking, it has been argued [108], but has longed periods of time in order to obtain an infusion of yet to be demonstrated experimentally, that drug-seeking is cocaine or heroin and this drug-seeking behaviour is not initiated under the control of the goal-directed R O affected by any pharmacological effects of the drug, since process, but with the onset of addiction becomes a

3 B.J. Everitt et al. / Brain Research Reviews 36 (2001) compulsive habit under the control of the S R process, Ant Cing, should also impair autoshaping as, indeed they even in parallel with an apparent reduction in those did, whereas NAcb shell lesions were without effect, subjective effects of the drug which initially established thereby revealing a dissociation in the involvement of self-administration [84]. This important issue warrants NAcb subregions in appetitive pavlovian conditioning more detailed investigation and will require the develop- [74]. Lesions of the dorsal striatum, some areas of which ment of novel approaches. also receive Ant Cing input, do not prevent animals from In contrast to these instrumental R O and S R pro- developing discriminative autoshaped approach responses cesses, Robinson and Berridge, through their developing [92], arguing for considerable neuroanatomical and func- Incentive Sensitization Theory [88,89] emphasize the role tional specificity within the striatal targets of afferents of pavlovian S O processes in drug seeking which, we from the Ant Cing. suggest, can take three forms [27,28]. Firstly, drug-associ- In fact, the Ant Cing and NAcb core appear to operate ated cues can elicit simple pavlovian approach responses, as part of a corticostriatal circuit underlying specific such as those manifest in so-called autoshaping proce- aspects of pavlovian conditioning, since a disconnection dures. Secondly, equally important is that drug-associated lesion of the two structures (a unilateral cingulate cortical stimuli, like other appetitive conditioned stimuli (CS), lesion and a NAcb core lesion on the contralateral side of exert a motivational influence on instrumental behaviour the brain) also impaired autoshaping. The deficits followwhether it is controlled by the R O or S R process. The ing bilateral Ant Cing and bilateral NAcb core lesions critical procedure for demonstrating this motivational differed, while the disconnection lesions resulted in a influence is the pavlovian-instrumental transfer (PIT) mixed pattern of deficits reflecting contributions from both design in which the impact of a separately trained CS on Ant Cing and NAcb core, supporting the contention that instrumental responses is assessed. Thirdly, drug-associ- the cortical and striatal nodes subserve different processes. ated CSs can act as conditioned reinforcers for instrumen- This also suggests that such a corticostriatal circuit does tal drug-seeking. Some of our experiments on the neural not operate in isolation, but is influenced by other neural basis of these pavlovian S O processes that we hypoth- processes at different levels of the circuit, such as the esize contribute powerfully to the development and per- major influence of dopamine (DA) specifically at the level sistence of addiction are summarized below (see also Refs. of the striatum or the suggested spiralling, ventral-to- [27,28]). dorsal, influence of corticostriatal circuits on each other [39] Appetitive pavlovian conditioning: autoshaping The amygdala is generally held to be a critical structure mediating various forms of appetitive and aversive con- Pavlovian conditioning is a fundamental learning mech- ditioning, but our investigation of the involvement of the anism that allows an animal to predict and adapt to future amygdala in autoshaping yielded perhaps surprising reevents based on previous experience. Autoshaping pro- sults. Thus, the CeN, but not the BLA, was shown to be vides a simple and quantifiable measure of appetitive the critical amygdala substrate since only CeN lesions pavlovian conditioning relatively unconfounded by other impaired autoshaping by selectively reducing the number forms of learning and allows investigation of the process of CS1 approaches [75]. This is not to deny the important by which environmental stimuli are associated with pri- role played by the BLA in emotional learning, but we mary reward to gain motivational or emotional valence suggest that its involvement may be with more complex measured in this task as discriminated approach to a representations or more flexible outputs than the reflexive reward-associated CS1, as opposed to a second stimulus production of a pavlovian conditioned response [27,42]. never having been associated with reward (CS2) There are now several strands of evidence indicating that [10,43,109,110]. This approach behaviour has been inter- selective lesions of the CeN consistently affect appetitive preted as a pavlovian sign-tracking response [43] as it pavlovian conditioning in situations where BLA lesions are lacks the flexibility and goal-directed nature of instrumen- without effect [31,32,52,94]. tal actions [119]. We have demonstrated an extensive What is not immediately clear is how the CeN interacts cortical subcortical network involving the Ant Cing, nu- with the Ant Cing NAcb core circuit, since, unlike the cleus accumbens (NAcb) core, central nucleus of the BLA, it does not project directly to the NAcb. However, amygdala (CeN) and mesolimbic DA system underlying the critical link may be provided by DA neurons in the this fundamental form of appetitive behaviour (see Ref. VTA, since not only does a 6-hydroxydopamine-induced [72]). DA-depleting lesion of the NAcb profoundly impair auto- Autoshaping depends upon the integrity of the Ant Cing, shaping [73], but the CeN projects richly to the DA but not posterior cingulate or medial prefrontal (including neurons of the VTA and substantia nigra [38,51]. Several prelimbic and infralimbic) cortex [10]. We hypothesized observations support the contention that the CeN exerts a that the Ant Cing may gain access to behavioural output regulatory influence over midbrain DA neurons, e.g. DA through the striatum, leading to the prediction that lesions lesions of the CeN or infusions of DA receptor antagonists of the NAcb, the major recipient of projections from the into the amygdala have marked effects upon extracellular

4 132 B.J. Everitt et al. / Brain Research Reviews 36 (2001) dopamine levels in the NAcb [12,44,54,57,100]. Further, Thus, systemic administration of the dopamine D2 receptor disconnecting the CeN from the DA innervation of the antagonist pimozide abolished PIT, whereas this treatment dorsal striatum impairs conditioned orienting, another form had no effect on instrumental incentive learning [25]; of appetitive pavlovian response [41]. amphetamine infused directly into the NAcb shell poten- Taken together, these results reveal a distributed neural tiated PIT [124], just as it potentiates responding with network underlying pavlovian approach behaviour that conditioned reinforcement (see below). This ability of involves the Ant Cing, NAcb core, CeN and a modulatory pavlovian CSs to potentiate instrumental behaviour in a influence of the mesolimbic DA system that is expressed way that is influenced by increased DA transmission in the within the NAcb. The precise functions of each node in NAcb again indicates an important influence of conditionthis network remain to be established definitively. But we ing on drug-seeking behaviour, since environmental suggest that the Ant Cing NAcb core system may mediate stimuli are very readily associated with the effects of pavlovian associative processes and give direction to self-administered drugs such as cocaine and these drug approach responses [28,76]. The CeN receives information cues are known strongly to influence drug-seeking [14,33]. about appetitive stimuli from a variety of sources (including the Ant Cing, high-order sensory cortices, BLA and 1.3. Conditioned reinforcement thalamus), so enabling it to orchestrate not only autonomic and endocrine responses via its projections to the hypo- Stimuli that have been associated with a reinforcer will thalamus and brainstem, but also different forms of arousal come to elicit the response produced by the reinforcer. processes dependent upon its projections to the chemically- This description of pavlovian conditioning expresses the defined systems of the reticular core of the brain [28,72]. learning as a mechanistic form of stimulus response Projections from the CeN to the DA neurons in the VTA, behaviour and does not necessarily assume that a more for example, may regulate the dopaminergic innervation of complex affective representation of the stimulus has been the NAcb and thereby behavioural activation that invigo- acquired. However, it is likely that in parallel to a rates approach responses. This regulation of NAcb DA mechanistic form of associative learning, an animal also may also enhance the coupling of the anterior cingulate develops a representation of the value of the predicted cortex NAcb core circuit that provides direction to ap- outcome. Stimuli that have acquired such value will act as proach responses [28]. The consistent demonstration of conditioned reinforcers and support instrumental goal-diactivation in the Ant Cing and amygdala in functional rected actions. Thus, pavlovian conditioned stimuli not imaging studies of cocaine and heroin addicts exposed to only elicit behavioural arousal and approach responses but, drug-associated stimuli [15,35,53] suggest that fundamen- by acquiring some of the properties of a goal, gain tal investigations of the neural substrates of appetitive motivational salience and thereby control over instrumental conditioning such as those summarised here will further behaviour as conditioned reinforcers [29,56,82]. clarify the neural basis of cue-induced craving, drug- We have studied this using a procedure that isolates the seeking behaviour and relapse. conditioned reinforcement process. It has two phases: firstly, as in the autoshaping procedure, a neutral stimulus 1.2. Pavlovian-to-instrumental transfer is paired with primary reward (e.g. water in thirsty subjects, sucrose in hungry subjects or intravenous Appetitive pavlovian CSs not only elicit behavioural cocaine) and the development of pavlovian conditioning is activation and approach responses, as summarized above, assessed by measuring discriminated approach to the CS1. they are also able greatly to enhance instrumental be- In the second phase, which is carried out in extinction, haviour [4,26,55,81]. To assess this influence, animals are thereby removing any influence of primary reinforcement, first trained to associate presentations of a stimulus (CS) two novel levers enter the testing chamber; responding on with delivery of primary reward (e.g. sucrose). During one of them results in presentation of the light CS1. training, animals learn to approach the sucrose delivery Responding on the second lever has no programmed location preferentially during the CS period (as in auto- consequence. The acquired motivational properties of the shaping). After this pavlovian conditioning, the animals CS to serve as a conditioned reinforcer are therefore are trained to lever press for the same sucrose reward in assessed by its ability to reinforce the acquisition of this the absence of the CS. Finally, in the test phase, the ability novel and arbitrary response. An important aspect of this of the CS to enhance lever pressing in extinction is process is that the control over behaviour by a conditioned assessed. The neural basis of this pavlovian-instrumental reinforcer is powerfully amplified by psychomotor stimultransfer (PIT) effect shares much in common with that ants and this effect has been shown to depend critically underlying pavlovian discriminated approach behaviour. upon the DA innervation of the NAcb [83,105,106], Thus, selective lesions of the CeN and NAcb core, but not specifically on its shell, rather than its core, compartment the BLA nor NAcb shell abolished the enhancement of [74]. However, even in the face of extensive DA depletion lever pressing during presentation of the CS [27,40,72]. from the NAcb, or general DA receptor blockade, rats still Moreover, the mesolimbic DA system also influences PIT. acquire a new response with conditioned reinforcement

5 B.J. Everitt et al. / Brain Research Reviews 36 (2001) [83,105,123]. That is, the mesolimbic DA system does not pends, the CeN may mediate a motivational influence on mediate conditioned reinforcement, but only its potentia- responding via the DAergic innervation of the NAcb, tion by stimulant drugs. through its projections to ascending DA systems origina- Thus, information about conditioned reinforcers must be ting in the midbrain. One last additional piece of data derived from another source, presumably one transferring extends our current picture of the neural network that such information to the NAcb where its impact can be underlies conditioned reinforcement and its dopaminergic gain-amplified by increases in DA transmission [29,83]. amplification. This concerns the role of the Ant Cing, Limbic cortical structures are the primary sources of implicated in the mnemonic retrieval of stimulus reininformation processed within the NAcb, most notably the forcer information in the autoshaping task. Lesions of the BLA, hippocampal formation (via the subiculum), pre- Ant Cing cortex did not impair temporally discriminated limbic and anterior cingulate cortices [18,37,45,46,61] and approach to the magazine or instrumental responding for we have studied their possible contributions to conditioned conditioned reinforcement (Cardinal, Robbins and Everitt, reinforcement. unpublished); nor were the potentiative effects of intra- Whilst the prelimbic cortex does not seem to contribute NAcb amphetamine affected by these lesions. Thus whilst to conditioned reinforcement, lesions of the amygdala and the Ant Cing is required for pavlovian approach to a CS1 subiculum had marked and different effects on responding in the autoshaping procedure, it does not appear to be for a conditioned reinforcer [9,11]. Lesions of the ventral involved in conditioned reinforcement. subiculum did not impair pavlovian or instrumental conditioning, as measured by either stage of the procedure, but instead blocked the ability of intra-nacb amphetamine to potentiate instrumental responding for the conditioned 2. Synthesis reinforcer [9]. The glutamatergic projections from the ventral subiculum to the striatum may therefore modulate From the above summary it can be seen that drug the potentiative effects of DA at the level of the striatum. addiction might be understood as the aberrant engagement Lesions of the BLA impaired the ability of the conditioned of these pavlovian and instrumental learning processes. reinforcer to support the acquisition of a new response: The amygdala, hippocampus, cingulate and medial prelesioned subjects failed to respond selectively on the lever frontal cortex are clearly involved in these associative producing the conditioned reinforcer, though intra-nacb processes and have been quite extensively studied. But it is amphetamine still potentiated responding [9,11]. BLA- increasingly clear that the striatum may also be involved in lesioned rats were not significantly impaired at magazine some forms of learning. For example, the NAcb core and approach during the pavlovian stage of the experiment its DA innervation have been shown to be involved in the [11], consistent with the lack of effect of BLA lesions on acquisition of pavlovian approach [47,76] and in inautoshaping (see above). Further, BLA lesions did not strumental learning [101], whereas a role for the dorsal impair instrumental responding per se [9] or responding on striatum (DS) in habit learning was originally suggested by habit-based instrumental tasks [8]. Impairments following Mishkin [60]. DA has been widely suggested to affect BLA lesions therefore appear to depend on whether the learning by its actions within the striatum [6,13,117] and behaviour requires a conditioned representation of the both DA and glutamate receptors have been implicated in reinforcer to perform the task [29,30,34]. In contrast, normal learning processes in striatal and limbic structures lesions of the CeN did not impair responding with con- [3,6]. Although NAcb DA may be especially responsive to ditioned reinforcement [91], but they did abolish the many drugs of abuse when given acutely to naıve subjects, potentiative effects of intra-nacb amphetamine (much like the fact that DA transmission is increased in both the the effects of ventral subiculum lesions) [91]. NAcb and DS when drugs are self-administered over In summary, then, the BLA, CeN and ventral subiculum extended periods of time may contribute especially powerare all involved in conditioned reinforcement and its fully to aberrant learning involving both structures. potentiation by the mesolimbic DA system, but their roles Dopaminergic neurons of the substantia nigra/ ventral are clearly dissociable: (1) the BLA subserves a process by tegmental area (SNc/ VTA) respond to unpredicted rewhich affective representations of stimuli are used to guide wards and with training, this response transfers to stimuli instrumental goal-directed behaviour, and the integrity of predictive of rewards [95,96]. Thus, by signalling reward this process is fundamental to the conditioned rein- prediction errors, DA may act as a teaching signal for forcement effect itself; (2) both the CeN and ventral striatal learning [96]. There is also evidence for dopasubiculum are essential for the potentiation of conditioned minergic consolidation of S R (habit) learning [70,71]. reinforcement by intra-nacb administration of stimulant Since DA-dependent processes of the DS are involved in drugs, but are not necessary for informational aspects of the development of S R habits [60,69,80,87], whilst DAthe conditioned reinforcement process. Whilst the ventral dependent NAcb processes are involved in incentive subiculum may provide the contextual background upon motivation/ reward [21,85,86], a qualitative difference may which the potentiation of conditioned reinforcement de- exist between these two striatal domains, albeit using

6 134 B.J. Everitt et al. / Brain Research Reviews 36 (2001) similar molecular and cellular mechanisms at the neuronal modelled as cue-induced reinstatement of drug-seeking level. after extinction [19,20,36,58,104,114]. The neural corre- Compulsive drug use is characterized by behaviour that lates of such cue exposure include conditioned changes in is inflexible, since it persists despite considerable cost to DA release in the NAcb as well as the altered expression the addict, may become dissociated from subjective mea- of genes and intracellular markers within the NAcb, sures of drug value [88], is elicited by specific environ- amygdala and Ant Cing [97,107,113]. Lesions of the mental stimuli [14], and yet, at least initially, involves amygdala, as well as intra-amygdala or intra-nacb infucomplex, goal-directed behaviours for procuring and self- sions of glutamatergic (especially AMPA) or dopaminergic administering a drug. One hypothesis is that limbic corti- receptor antagonists can prevent the reinstatement of cal ventral striatopallidal circuits that underlie goal-di- extinguished cocaine-seeking behaviour induced by exporected drug-seeking actions, mediated by the R O process, sure to drug-associated stimuli [16,17,36,59] or diminish eventually consolidate habitual S R drug-seeking through cocaine-seeking under a second-order schedule of cocaine engagement of corticostriatal loops operating through the reinforcement [23]. dorsal striatum. This progression from action to habit may It may prove possible, therefore, to prevent relapse in have its neural basis within the recently described spiral- human addicts by systemically administering drugs that ling loop circuitry of the striatum, by which each striatal diminish the motivational properties of drug-associated domain regulates its own DA innervation and that of its cues, thereby preventing lapses into drug-taking. We have adjacent domain in a ventral-to-dorsal progression [39]. shown that a partial agonist at D3 DA receptors can greatly Thus, the NAcb shell regulates its own DA innervation via diminish cocaine-seeking behaviour [78], but it remains projections to the VTA, and also that of the core. The core unclear whether this effect is mediated by blockade of D3 in turn regulates its own DA innervation via projections to receptors within the NAcb, the amygdala or autoreceptors the VTA, and also that of the next, more dorsal tier of the on the mesolimbic DA neurons themselves. One advantage DS via projections to the SNc and so on [39]. Chronically of drugs acting at the D3 receptor is that its distribution in self-administered drugs, through their ability to increase the brain is restricted to these few sites [78,102] and so striatal DA, may consolidate this ventral-to-dorsal striatal unwanted side effects of such drugs are minimal. It has not progression of control over drug-seeking as a habitual form been established whether systemically administered anof responding. tagonists at AMPA or NMDA glutamate receptors can be The transition between control by the R O process to used to prevent cued relapse without general effects on S R habits may also depend upon the executive control behaviour. A better understanding of the neural mechaprovided by descending influences on striatal mechanisms nisms though which pavlovian and instrumental learning from the prefrontal cortex (PFC) [99]. Indeed, recent processes may be engaged aberrantly to underlie drug evidence suggests that chronic drug administration leads to addictive behaviour holds great promise for the developpathological changes in PFC neuronal architecture in rats ment of novel treatments in the future. [90], characteristic post mortem neurochemical pathology in the orbital prefrontal cortex (opfc) of amphetamine abusers [120] and major changes in the functional activa- Acknowledgements tion of the opfc in cocaine addicts [111], each of which could have rebound effects on drug-seeking/ taking be- The research summarised here is supported by an MRC haviour as well as on cognitive decision making [93]. We Programme Grant (G ) to BJE, TWR and AD and have also shown that excitotoxic lesions of the mpfc was carried out within the MRC Co-operative in Brain, disinhibit drug-, but not food-seeking behaviour [115]. Behaviour and Neuropsychiatry. We gratefully acknowl- However, much more needs to be understood about the edge the major contributions of Helen Alderson, Mercedes ways in which different sectors of the PFC interact with Arroyo, Rudolf Cardinal, Patricia Di Ciano, Jeremy Hall, their striatal domains in the context of drug addiction [79]. Rutsuko Ito, Athina Markou, Cella Olmstead, John Parkin- Another important potential consequence of the aberrant son, Maria Pilla, Patricia Robledo and Rachel Whitelaw to learning engendered by chronic drug self-administration is this work. the strong and persistent propensity to relapse, especially in the presence of drug-associated stimuli in the addict s environment. Even following protracted abstinence from References drug-taking, relapse can be seen as a logical consequence of the conditioning processes that underlie compulsive [1] H.L. Alderson, T.W. Robbins, B.J. Everitt, Heroin self-administration drug-seeking, since this habit can be reactivated and under a second-order schedule of reinforcement: acquisition and motivated by drug-related cues. In humans, this may maintenance of heroin-seeking behaviour in rats, Psychopharmacol- ogy 153 (2000) involve retrieval from memory of vivid drug-related [2] M. Arroyo, A. Markou, T.W. Robbins, B.J. Everitt, Acquisition, experiences, manifested as craving, that lead to further maintenance and reinstatement of intravenous cocaine self-adminisdrug-seeking and taking [15,35]. In animals, this has been tration under a second-order schedule of reinforcement in rats:

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