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Neurobiology of craving, conditioned reward and relapse

Friedbert Weiss
Chronic vulnerability to relapse is a formidable challenge for the treatment of drug addiction. The neurobiological basis of relapse and its prevention has, therefore, attracted major attention in addiction research. Current conceptualizations of addiction recognize craving as a central driving force for ongoing drug use, as well as for relapse following abstinence. Progress has been made in understanding experiential factors, neurocircuitry components and signaling mechanisms that mediate conditioned drug-seeking behaviour, craving and long-lasting susceptibility to relapse. Importantly, stress contributes to drug craving, and there is evidence for overlap between the neural and neuroendocrine mechanisms implicated in drug desire evoked by drug cues and stress. Recent research has substantially advanced our understanding of the neurobiological factors responsible for drug craving and relapse, with promising therapeutic implications.
Addresses The Scripps Research Institute, Department of Neuropharmacology (CVN-15), 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Corresponding author: Weiss, F (bweiss@scripps.edu)

research has, therefore, shifted towards identifying the experiential and neurobiological mechanisms responsible for the chronically relapsing nature of addiction. Major precipitating factors for relapse include drug craving and stress [1,2], with an increasing recognition of cognitive factors such as pre-attentive automatic reactions, and attentional bias related to previous drug experiences [3,4,5]. These risk factors are further aggravated by protracted withdrawal symptoms resulting from druginduced neuroadaptation, but also by conditions such as psychiatric comorbidity, socioeconomic conditions and perceived drug availability [1,6,7]. Here, recent advances in both the neurocircuitry and the neurochemical and molecular bases of craving and relapse are reviewed, with emphasis on two fundamental questions: firstly, what factors are responsible for the distinctly compulsive nature of drug-seeking and craving, as opposed to behaviour motivated by natural rewards essential for survival and well-being; and secondly, what long-term changes develop in the brain during chronic drug use that maintain craving and relapse risk through years of abstinence and rapidly re-establish fullblown dependence after resumption of drug use? This review focuses predominantly on cocaine and ethanol as examples.

Current Opinion in Pharmacology 2005, 5:9–19 This review comes from a themed issue on Neurosciences Edited by Graeme Henderson, Hilary Little and Jenny Morton Available online 21st December 2004 1471-4892/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2004.11.001

Associative learning as a factor in craving and relapse
Critical for craving and relapse is the process of associative learning, whereby environmental stimuli repeatedly paired with drug consumption acquire incentive-motivational value, evoking expectation of drug availability and memories of past drug euphoria [8–10]. Conditioned responses to such stimuli can activate brain reward mechanisms [11] and have been implicated both in maintaining ongoing drug use and in eliciting drug desire during abstinence, precipitating relapse. The definition of craving and its measurement, as well as the predictive link between craving and relapse, is still a matter of some debate [12,13,14]. Moreover, as a hypothetical construct, craving is difficult to model with functional equivalence in animals [14]. However, reactivity to drug cues has established significance for craving in clinical settings. These conditioned responses represent a mechanism leading to craving, and can therefore be exploited to study this specific aspect of craving in animals [8]. Functional brain imaging in humans ([15–17]; see review by Lingford-Hughes, this issue) as well as lesion and site-specific pharmacological manipulations in animals [9,10,18] have implicated an interconnected set of cortical
Current Opinion in Pharmacology 2005, 5:9–19

Abbreviations BDNF brain-derived neurotrophic factor BLA basolateral amygdala CRF corticotropin-releasing factor CS conditioned stimuli HPA hypothalamic-pituitary-adrenal LH lateral hypothalamus MAPK mitogen-activated protein kinase mGluR metabotropic glutamate receptor NAc nucleus accumbens N/OFQ nociceptin/orphanin FQ OFC orbitofrontal cortex PFC prefrontal cortex PLC prelimbic cortex VTA ventral tegmental area

Introduction
Relapse is a phenomenon pivotal for the understanding and treatment of drug addiction. The focus of addiction
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Importantly. The NAc. such that modeling craving and reinstatement alone is not sufficient for investigating the chronic and compulsive nature of addiction [8]. but not shell.46.e. The OFC has been found to modulate cocaine-seeking in a subregionspecific manner. Even stimuli present during a single cocaine experience elicited drug-seeking for up to one year [45]. rats expressing conditioned preference for a cocaine-paired environment (i. has long been considered critical for drug-seeking and reinforcement. Existing evidence favours a differential role for these subregions in reinstatement and second-order schedule performance maintained by discrete conditioned stimuli (CS) versus reinstatement elicited by contextual stimuli. Extinction substantially decreased reinstatement (as measured by CS-maintained responding on a second order schedule) www.e. anterior cingulate. dopaminergic terminals in the NAc core and the BLA might differentially regulate CS-maintained cocaine reinforcement [28]. which are defining features of addiction.31]. recovery of extinguished drug-seeking by contextual stimuli is dependent upon the NAc shell. Overall.47].33] through its rostral subdivision [34]. a ‘slip’ into limited drug use is unimportant for ultimate therapeutic success.sciencedirect. New understanding has accrued on the function of the OFC and PLC in drug-related learning. However. the latter responding indiscriminately to the drug cue or neutral stimulus [29]. Reinstatement by drug cues is resistant to extinction and persists over months of abstinence [42. Selective inactivation of the NAc core. neural substrates for reinstatement associated with contextual and explicit CS overlap. nucleus accumbens (NAc) and. Major components of this circuitry include the orbitofrontal cortex (OFC). in contradiction to the effects of dopamine receptor blockade in the BLA [25]. abolished cocaine CS-induced reinstatement [24]. input from the rostral BLA to the NAc shell is a neural link essential for encoding the motivational value of drug-associated contextual stimuli [29.35]. The decreased activation of excitatory PLC efferents may add to the functional defects in prefrontal cortical regions that develop with chronic cocaine use [37–40]. more recently. but also show distinct differences. which is thought to participate in consolidating stimulusresponse habits via the engagement of corticostriatal loops [10]. Novel data also implicate the dopaminergic projection from the ventral tegmental area (VTA) to the NAc core in associative processes that influence conditioned responding under second order schedules [28]. and lack of judgement and risk assessment [41]. Shell neuron responses to the drug cue were still evident after four weeks of abstinence.44]. whereas the shell appears essential for the psychomotor stimulant effects of cocaine [26]. the shift in activation patterns of PLC cell populations could contribute to impaired impulse control.27].com . a functionally heterogeneous structure consisting of core and shell subregions (for review. illustrating that the neural representation of the motivaCurrent Opinion in Pharmacology 2005. however. inactivation of the dopaminergic projection from the VTA to the BLA failed to interfere with the conditioned reinforcing effects of cocaine CS [28]. a contextual stimulus) showed increased activation of inhibitory GABAergic interneurons. Determinants of craving and relapse as persistent and compulsive phenomena Clinically. Thus.32. the dorsal striatum. neurons in the shell exhibited significantly greater activity than those in the core. functional integrity of the core is required for the acquisition of conditioned cocaine reinforcement. the behavioural significance of which awaits clarification. with CS-maintained reinstatement controlled by the lateral OFC and drug-induced (i. or without. paired with decreased excitatory output from this site [36]. Moreover. 5:9–19 tional significance of these stimuli is highly resistant to decay [29]. Thus. Substantial advances have been made in elucidating key components and signaling mechanisms within this circuitry that regulate specific aspects of drug-seeking using animal models of conditioned reinforcement and conditioned reinstatement (see Boxes 1–3). and blockade of glutamate receptors in the NAc core eliminated conditioned reinforcement by cocaine CS on a second order schedule [25]. hippocampus. Furthermore.43. Importantly. inactivation of the dorsomedial prefrontal cortex (PFC) and BLA impaired reinstatement by cocaine CS [30. In contrast to CS-maintained conditioned reinforcement and reinstatement. whereas inactivation of the dorsal hippocampus was selective for contextual reinstatement [30]. Evidence has accumulated that drug-seeking in animals resembles along several dimensions the compulsive nature of addiction in humans. Considering the ‘executive function’ of the PFC that includes risk-benefit analysis and suppression of limbic impulses. basolateral amygdala (BLA). recent data also implicate the BLA in contextual reinstatement [30. presentation of drug-associated CS. see [23]). ‘priming’) reinstatement by the medial OFC [31]. the glutamatergic projection from the BLA to the NAc core was found to be critical for the expression of cocaine CS-maintained second order schedule performance [25. During reinstatement evoked by a cocaine-predictive contextual stimulus. In the PLC.10 Neurosciences and limbic brain regions in associative learning underlying craving and relapse (see Table 1). The behavioural significance of this ‘incubation’ effect [48] was scrutinized by isolating the respective contribution to reinstatement of simply terminating access to cocaine versus subjecting rats to extinction of cocaine-reinforced responding with.43. the ‘intensity’ of conditioned reinstatement increases during the initial months of abstinence [42. prelimbic cortex (PLC).

Neurobiology of craving. modulating HPA axis activity CRF-rich nucleus and ‘apex’ of the HPA stress axis.Presumed role in the switch from ‘action to habit’ (i. Key component of the extrahypothalamic CRF stress system reciprocally connected to the BNST Final common pathway processing stress and anxiety responses.sciencedirect. and their role in drug addiction. integrating converging input from limbic sites related to appetitive and activational aspects of rewards for output to effector sites.Conditioned reinforcement . detection/evaluation of action–outcome relationships. The BNST also projects heavily to the PVN.CS-based reinstatement NAc shell . Retrieval of episodic memories. craving and relapse (italicized).Site implicated in Group II mGluR-mediated contextual reinstatement .CS-based reinstatement .or ethanol-addicted individuals .Conditioned reinforcement . including attribution of emotional and motivational value to internal and external stimuli guiding appropriate response selection. Stress-related addictive behaviour is thought to be related to activation of the HPA axis by CRF .Contextual reinstatement . Regulation of autonomic and endocrine function . Fine-tuning motoric functions.Conditioned reinforcement . the transition from drug abuse to drug addiction) Origin of the mesocorticolimbic dopamine projection . cue. Conditioned emotional learning. working memory.Stress-induced reinstatement .Contextual reinstatement Limbic-motor interface.CS-based reinstatement .Molecular neuroadaptations linked to escalated cocaine intake Processing of behavioural and physiological responses to stress.Molecular neuroadaptations following chronic cocaine with implications for craving and relapse .e.Cue-induced craving (human functional brain imaging) Attention.Contextual reinstatement . NAc core .Putative final common pathway at the cortical level for stress-.Cue-induced craving (human functional brain imaging) Contextual learning and memory consolidation. Participation in the translation of motivation into action.Contextual reinstatement . Assessment of reward value against previous experience influencing action and choice .Drug cue exposure leads to HPA axis activation correlated with craving in cocaine. CRF is the major stress-regulatory molecule in the brain and integrates behavioural.Inteference with HPA axis activation prevents cue-induced reinstatement Anterior cingulate cortex Prelimbic cortex Basolateral amygdala Hippocampus Nucleus accumbens Dorsal striatum Ventral tegmental area Lateral hypothalamus Central nucleus of the amygdala Bed nucleus of the stria terminalis (BNST) Paraventricular nucleus of the hypothalamus Hypothalamicpituitary-adrenal axis www.and drug-induced craving and reinstatement . Associative learning linked to rewarding and aversive stimuli. Key component of the extrahypothalamic stress system. Bain region Prefrontal cortex Orbitofrontal cortex Function Executive and decision-making functions based on the recognition of survival-related challenges.CS-maintained reinstatement .Stress-induced reinstatement . Integration of emotion and natural drive states with behaviour.Increased in brain reward function by exposure to cocaine cues .e. and execution of goal-directed actions. Attention and cognitively demanding information processing. Conditioning of contextual stimuli to fear or reward . Consolidation of stimulus-response habits via corticostriatal loops .com Current Opinion in Pharmacology 2005.CS-based reinstatement .Cue-induced craving (human functional brain imaging) Processing of emotionally significant stimuli guiding conditioned and unconditioned approach or avoidance behaviour .Impaired brain reward function associated with escalated cocaine intake .Molecular neuroadaptations following chronic cocaine with implications for craving and relapse Regulation of ingestive behaviour Sensitive site for the rewarding effects of electrical brain stimulation reward and changes in brain reward function as measured by intracranial self-stimulation reward thresholds . conditioned reward and relapse Weiss 11 Table 1 Description of the major function of brain regions covered in this review.Cue-induced craving (human functional brain imaging) Part of the extrapyramidal motor system. initiating and sustaining behavioural responses.Conditioned reinforcement . endocrine and autonomic responses to stress Release of CRF from PVN neurons projecting to the anterior pituitary results in secretion of ACTH (i. response initiation and inhibition.Conditioned reinforcement .Contextual reinstatement . predominantly corticosterone. Regulation of autonomic and endocrine function .Cue-induced craving (human functional brain imaging) Processing of pleasure and pain. activation of the HPA axis) leading to secretion of adrenal glucocorticoids. 5:9–19 .

therapies. showed ‘incubation’). Non-contingent exposure to contextual cues readily elicits reinstatement. Following extinction of CPP. Owing to their predictive nature for drug availability. responsecontingent). in contrast with the well-established inhibition of appetitive behaviour by aversive stimuli (‘conditioned suppression’). as a measure of drug craving. Rats prone to ‘addiction’ on one index of vulnerability (cocaine ‘priming’) also proved more susceptible to other addiction-like behaviours. Thus. one related to personal experience) for the development of compulsive drug-seeking is that consumption of a drug during withdrawal. ‘reinstatement’ tests are conducted in which the degree of recovery of responding at the previously drug-paired operandum. tactile or visual stimuli in the drug self-administration environment) for conditioning that are not discretely paired with drug infusions nor contingent upon a response. ambient olfactory. second order schedules have proven highly effective for investigating the significance of conditioning factors in ongoing drug-seeking and taking (for review. compared with one week of abstinence alone. without further drug delivery). one of the hallmarks of substance dependence.e. before drug delivery that can be operationally defined. Thus. a measure of ‘drug-seeking’. including escalation of cocaine intake. the inflexible dimension that characterizes addiction can readily be demonstrated in animals but requires prolonged drug access. see [19]). is operationally defined as a measure of craving or relapse or. auditory. An important experiential factor (i. confirming original findings that such exposure regimens are critical for the transition from drug use to dependence [50]. drug-reinforced responding (technically referred to as ‘operant’ or ‘instrumental’ responding) is ‘extinguished’ by ceasing to reinforce responses by drug delivery and withholding presentation of the CS. lead to the initiation of reponding) but additionally. also become associated with the rewarding effects of the drug and thus acquire incentive-motivational value (i. www. a tone.e. Another contextual reinstatement procedure is based on learning of a conditioned place preference (CPP) for an environment paired with experience of the drug. 5–20 s) presentation of one or more environmental stimuli (e. whereas this is not the case with non-contingent CS presentation in CS-based reinstatement models [21. through different neural circuitries or activation patterns [9]. These two variants of associative learning probably occur simultaneously during drug use but may be coded. elicit memories of previous drug euphoria and the ‘magnitude’ or value of the rewarding effect of drug consumption. during learning. eliminating drug availability following extinction might. more generally. Animals are first trained to self-administer a drug.g. both drug administration and presentation of the CS are contingent upon a response by the animal (i. with time. see [20]). CS-maintained responding in the extinguished group was increased (i. In this procedure.e. In contemporary applications of this procedure. an event inextricably linked to addiction. 20–60 CS-reinforced responses). cue light or both). Drug-seeking in animals is also consistent with defining features of addiction other than persistence. Subsequently. diminishing the effects of extinction. these stimuli are particularly powerful in eliciting drugseeking and reinstatement. The principal measure of interest in this procedure is the degree of conditioned reinforcement maintained by the drug-paired CS. Rats with a history of prolonged. however. by virtue of their presence during drug consumption.e. Thus.22]. which then leads to a single administration of the drug reinforcer itself. and was identical to rats not subjected to extinction [46].12 Neurosciences Box 1 Animal models of craving and relapse (1): CS-based extinction-reinstatement model. except that it utilizes contextual stimuli (i. 5:9–19 . The most widely employed method to model craving and relapse (for review. However.e. is substantially lower than that maintained by delivery of the drug and deemed incidental rather than motivated by expectation of obtaining the drug). cocaine self-administration failed to show suppression of CSmaintained drug-seeking when concurrently presented with a conditioned stressor [44.g. the re-establishment (technically termed ‘renewal’) of CPP can be operationalized to reflect a measure of relapse and craving. animals are trained to respond at a lever or other ‘operandum’ where completion of each response requirement (i. The time since cessation of drug use might therefore be an important factor in determining the efficacy of cue extinction Box 2 Animal models of craving and relapse (2): second order schedule of reinforcement.g. Because of this dual property. depending on the experimental objective) results in delivery of a small intravenous (in the case of opioids or psychostimulants) or oral (in the case of ethanol) dose of the drug. Although not a formal equivalence model of relapse because of typically lacking extinction and abstinence manipulations [14]. both types of stimuli maintain responding at a previously active drug operandum [21]. Box 3 Animal models of craving and relapse (3): contextual extinction-reinstatement model. Animals then are subjected to a procedure in which only the CS is available response-contingently until completion of a predetermined response-requirement (e. Once initiated. until completion of the response requirement leading to the next drug injection.e.49]. responses at the drug operandum are reinforced only in the presence of these stimuli. whereupon the contingency reverts again to the non-drug-reinforced schedule component with response-contingent presentation of the CS only. Multiple contextual reinstatement procedures are employed. conditioned reinstatement and maintenance of cocaine-seeking despite increased work requirements [44]. This is another widely employed model of ‘craving’. Consequently. This model is identical in most aspects to the CS-based reinstatement model.e. augment the efficacy of drug cues to facilitate reinstatement.sciencedirect. The most prevalent ‘contextual’ reinstatement model utilizes cues referred to as ‘discriminative stimuli’ where. after four weeks of abstinence.e. now maintained by response-contingent presentation of the conditioned CS only (i.com Current Opinion in Pharmacology 2005. at least in part. Each response producing a drug injection is paired with brief (e.e. extinction sessions are conducted daily until responding ceases (i. response-contingently paired with presentation of a CS. again. but not limited. these stimuli ‘set the occasion’ for engaging in reward-seeking behavior (i. Once reliable drug self-administration is acquired. one or more responses. drug-related cues in rats having experienced prolonged cocaine exposure sustain drug-directed behaviour despite adverse consequences. referred to as CS.

its reinforcing efficacy particularly during subsequent withdrawal states.or cocaine-associated contextual cues. as well as transient elevation of cyclin-dependent protein kinase 5 in the VTA [61]. PFC and caudate-putamen that persists for months [63–65] — structural changes with a presumptive role in sensitization and the persistence of craving and relapse risk. a pathway involved in long-term potentiation and synaptic plasticity. Such generalizations would dramatically contribute to the compulsive nature of drug addiction. Chronic cocaine (or morphine) also alters postreceptor signaling cascades for BDNF in the meso-accumbens pathway. timedependent variations in CS-induced reinstatement of reward-seeking might be common to drug and natural rewards but. suggesting that the nature of the reward (drug versus natural) determines whether compulsive behaviour resistant to adverse environmental events develops [44. this issue). see [62]). also linked to proliferation of dendritic sprouting [66]. eliminated conditioned suppression of ‘reward-seeking’ by a footshock-predictive cue.. whereas this was not the case in dependent rats not having experienced ethanol during withdrawal [53. resulting in reduced levels of this amino acid during cocaine withdrawal. but not sucrose. by extrapolation from data above [46]. Prolonged exposure to cocaine. The first — cocaine-induced alteration in cystine-glutamate exchange in the NAc — regulates basal extracellular glutamate levels. Further understanding of the mechanisms contributing to the differential control of ‘normal’ appetitive versus compulsive drug-seeking behaviour might be gleaned from selective effects of pharmacological manipulations. This experience can enhance the incentive value of the drug and. including changes in synaptic strength. Withdrawal from prolonged cocaine self-administration is also associated with lasting increases in glutamate N-methyl-D-aspartate receptor 1 and GluR2 receptor subunits in the NAc and VTA.55]. This mechanism might also be relevant for cue-induced craving and relapse. a member of the opioid peptide family. considering that drug consumption during withdrawal is likely to increase not only the incentive value of the drug but also the conditioned incentive value of drugrelated stimuli. and was still evident after two months of abstinence [69]. showed greater conditioned reinstatement. a hypothesis supported by long-lasting potentiation of reinstatement following intra-VTA application of BDNF [58]. thus supporting the hypothesis that increases in both BDNF and MAPK levels during cocaine withdrawal represent molecular neuroadaptations contributing to craving and relapse associated with drug cue exposure. Thus. one of which sustains MAPK activation during prolonged cocaine abstinence [62]. Increased expression of brain-derived neurotrophic factor (BDNF) is a probable mechanism for the ‘incubation’ of conditioned reinstatement [42].60]. reversed conditioned reinstatement by ethanol.49].54]. Increased BNDF expression initiates a plethora of signaling cascades with implications for addiction (for review. The activation of cyclin-dependent protein kinase 5.sciencedirect. because not only the ethanol CS but also footshock and a conditioned stressor exacerbated reinstatement in rats having consumed ethanol while in withdrawal. appetitive behaviour motivated by palatable sweet solutions [56. these molecular changes are promising Current Opinion in Pharmacology 2005. A group II metabotropic glutamate receptor (mGluR) agonist and nociceptin/ orphanin FQ (N/OFQ). Although a behavioural function for these neuroadaptations has been demonstrated only for cocaine-induced reinstatement.Neurobiology of craving. whereas the same stimuli paired with a palatable sweet solution remained effective for only three months [45]. an effect implicated in susceptibility to relapse [68]. and presented with ethanol CS three weeks after withdrawal [52].47]. neural signaling and dendrite formation.57]. incubation of CS-induced reinstatement developed with stimuli conditioned to either cocaine or sucrose [42. Cocaine-associated contextual stimuli elicited reinstatement for one year.com . ethanol-dependent rats allowed to self-administer alcohol during withdrawal. Sound support for this hypothesis exists in animals [51]. processes that have been implicated in development of addiction [59. Molecular neuroadaptations in two other regulatory systems are also of interest. but not in rats without this drug history [52. conditioned reward and relapse Weiss 13 introduces learning about a previously latent incentive dimension of the drug — its capacity is to alleviate physically or emotionally adverse states. we must recognize differences that exist between the stimulus control of behaviour motivated by natural versus drug rewards (see chapter by Salamone et al. Neurobiological basis of long-lasting susceptibility to relapse Central to the understanding and treatment of craving and relapse are cellular and molecular neuroadaptations that mediate enduring associations between drugs and associated stimuli. Conversely. 5:9–19 Craving and ‘seeking-behaviour’ associated with drug versus natural rewards To understand drug compulsion. The role of BDNF in reinstatement appears to depend critically upon recruitment of mitogen-activated protein kinase (MAPK) signal transduction [58]. The enhanced incentive value of drugs and associated environmental stimuli through withdrawal-related learning could generalize to other states of aversion and negative affect. therefore. Indeed. Repeated cocaine increases dendritic sprouting in the NAC. might be a contributing factor. without altering www. The second — upregulation of an activator of G protein signaling —showed significant elevation in the PFC and NAc after only one week of cocaine exposure. Pharmacological interference with MAPK signaling reduces preference for a cocaine-paired environment [67]. could be driven by ‘incubation’ of ‘spontaneous recovery’ as an underlying process.

74. It is unclear.g.e. might not be specific to addiction-related events but components of ‘normal’ circuits activated to a greater degree. although complex and influenced by multiple factors.84]. see [81]). as well as for neuronal excitability and glutamate transmission (cited as unpublished in [50]).but not sucrose-seeking behaviour [42]. Brain regions activated by drug cues.86]. increases mesocorticolimbic dopamine transmission. Interestingly.14 Neurosciences targets to explore with respect to a role in cue-elicited craving and relapse. whereas cell populations activated only by water reinforcement were not (reviewed in [76]). scriptional profiling by DNA microarray revealed that escalated cocaine intake is associated with alterations in transcripts relevant for neurite extension and synaptogenesis. activated during cocaine-reinforced responding. therefore. and hypothalamic paraventricular nucleus (reviewed in [2]). cueand drug-induced reinstatement [87]. dysphoria. Both aversive and appetitive events are processed by interactions among limbic subcortical and prefrontal cortical regions. with the establishment of a new hedonic set point (for review.78]). were also responsive to cocaine CS. Novel evidence shows that increased cocaine intake (‘escalation’) that develops with prolonged drug exposure [50] leads to long-lasting counteradaptive deficits in brain reward function which reduce the hedonic impact of cocaine [79]. are thought to be processed via the same neurocircuitry [18. see [50. TranCurrent Opinion in Pharmacology 2005. Thus. pharmacological manipulation of this system modifies both heroin reinforcement and conditioned reinstatement [73]. therefore. More importantly. NAc neurons. Several theoretical views exist on the motivational mechanisms by which stress provokes relapse as discussed in several excellent reviews [82. whether motivated by drugs of abuse or natural rewards. corticosterone synthesis inhibition and blockade of CRF1 receptors in rats attenuated cocaine CS-induced reinstatement (i. including comparable increases in negative affect and anxiety [85. indicative of a role for stress (i. Different neurocircuitries for drug versus natural reward? Conditioned responses. including the BLA and OFC. what differentiates neural signaling regulating normal appetitive behaviour versus pathological behaviour resulting from drug-related conditioning. Footshock (as a model of stress) reinstates extinguished responding previously maintained by drugs of abuse. synaptic rearrangement and altered neural excitability in the LH could play a role in compulsive cocaine-seeking [50] (for related discussion. via HPA axis activation. evidence for overlap between the neural substrates mediating stress www.72]. as increased BDNF expression is linked to incubation of conditioned cocaine. Stress as a source of craving Stress. however. cocaine and alcohol addition [71. These observations implicate overlap between neural substrates controlling craving evoked by drug cues and stress. and may reflect either the creation of new motivational states such as those produced by withdrawal-related learning [74] or the tilting of processes that normally govern responding for natural rewards towards drug-directed behaviour. Positron emission tomography imaging data of craving in heroin addicts indicate that both drug and non-drug stimuli activate brain attentional and memory circuits (primarily the anterior cingulate and OFC) but with stronger effects evoked by drug cues [77].sciencedirect. Lastly.75]. Increases in ionotropic and mGluR subunits during withdrawal support such changes in glutamate transmission during prolonged cocaine exposure [80]. cell adhesion and nerve regeneration.83. Consistent with these findings.e. findings that support the allostatic view of addiction. with ultimate effects on extrahypothalamic and neuroendocrine stress responses through direct and indirect connections with the bed nucleus of the stria terminalis.com Dysregulation of hedonic homeostasis A widely held position in addiction theory views craving and relapse as an opponent motivational process to avoid negative affect (e. Finally. activation of both brain motivational circuits and stress-regulatory systems by drug cues and stress implicates common neural substrates through which these challenges enhance drugseeking. Of interest here is the growing evidence that drug cue and stress manipulations induce a similar pattern of craving and cue reactivity. an emerging neuropharmacological mechanism in craving and relapse is the endocannabinoid system that functionally interacts with numerous other brain neurotransmitter systems with established roles in drug-seeking and addiction [70]. Allostasis has also been linked to dysregulation in molecular signaling systems. defined as a state of progressive deviation of motivational regulatory systems by chronic drug use from their normal function. Exposure to drug cues in cocaine-dependent subjects produced increases in both craving and corticotropin-releasing factor/hypothalamic-pituitary-adrenal (CRF/HPA)-axis-dependent behavioural and physiological measures of stress [86]. The most recent conceptualization of this process focuses on the development of allostasis. Stress. Differential activation of BDNF-induced signaling might be a contributory factor. gene transcript changes in cocaine ‘escalated’ rats were confined largely to the lateral hypothalamus (LH). a measure of ‘craving’). The endocannabinoid system has been implicated in opiate. anhedonia and anxiety). has an established role in relapse [2]. which is a consequence of withdrawal from most drugs of abuse. HPA axis activation) in the responsereinstating actions of drug cues [22]. central nucleus of the amygdala. 5:9–19 . with the PLC representing a possible common pathway for stress-. Transient lesion and site-specific pharmacological manipulation of PFC regions have implicated the PLC and OFC as components of a circuitry mediating footshock-induced drug-seeking.

whereas abstinent drug users are frequently exposed to multiple external risk factors. Behaviourally. Importantly. craving and relapse show that repeated withdrawal from escalated cocaine intake leads to long-lasting deficits in brain reward function. these results also verified the selectivity of Group II mGluR activation for drug-seeking behavior. which exerts strong CRF antagonist actions in the bed nucleus of the stria terminalis [91].Neurobiology of craving. Lastly. Current Opinion in Pharmacology 2005. Moreover. Update Conclusions The past three years have seen major advances in understanding of the experiential and neurobiological basis of craving and vulnerability to relapse. as LY379268 had no effect on responding for oral sucrose. investigation of how interactions among risk factors exacerbate the likelihood of resumption of drug use could substantially advance our current understanding of the relapse process. It is therefore likely that the probability of relapse varies as a function of the number and intensity of risk factors operative at any given time. major gaps remain in our knowledge of the control of craving and relapse. For example. impervious to punishment. Several agents that attenuate conditioned reinstatement [56. while experiencing varying degrees of protracted withdrawal symptoms. Risk factors for relapse are typically studied in isolation.57] also have marked ‘anti-stress’ and anxiolytic profiles. a predictive relationship between subjective reports of stress or craving and subsequent drug use is a matter of some dispute [2. The author would like to thank Mike Arends for his editorial assistance. both in incubation and vulnerability to relapse in general. the presumptive role of the LH in the consequences of escalated drug intake will require demonstration of a link between gene expression changes and ‘allostatic load’. only the time profile of BDNF corresponded well with incubation of drug-seeking. Childress AR.12.com Recent work has confirmed that Group II mGLuR activation by the mGlu2/3 agonist LY379268 attenuates context-induced reinstatement of heroin-seeking [94]. reinstatement of alcohol-seeking was found markedly enhanced when rats were subjected to footshock stress before response-contingent exposure to ethanol CS [52. DA08467 and DA017097. National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants AA10531 and AA014351. Interactions among risk factors for craving and relapse Although craving and stress are undoubtedly important for relapse. both with regard to a mechanistic role in addiction and as drug targets for relapse prevention.55]. Systematic investigation of such interactions could substantially advance current understanding of the relapse process. Both the individual and interactive effects of stress and the ethanol cue were greatly augmented in previously ethanol-dependent rats tested three weeks after withdrawal. References and recommended reading Papers of particular interest. conditioned reward and relapse Weiss 15 and drug cue effects exists also at the pharmacological level. O’Brien CP.sciencedirect. the important function postulated for the dorsal striatum in consolidating addiction-related stimulusresponse habits would benefit from confirmation as to whether this role applies specifically to ongoing drugseeking maintained by conditioned reinforcers or also to relapse. providing crucial support for the utility of animal models as tools for investigating the neural basis of specific aspects of addiction. These include Group II mGluR agonists [88–90] and N/OFQ. as well as in glutamate receptor subunits and gene transcripts linked to regulation of excitatory neurotransmission. Clearly. published within the annual period of review. Acknowledgements The author acknowledges National Institutes of Health funding through National Institute on Drug Abuse grants DA07348. This question is important because inactivation of the dorsolateral striatum failed to interfere with conditioned reinstatement of cocaine-seeking following extinction and abstinence [93]. Novel data indicate strong overlap between neural substrates controlling drug desire evoked by drug cues and stress. prolonged exposure to drugs of abuse in animals has consequences consistent with defining features of substance dependence in humans. have been highlighted as:  of special interest  of outstanding interest 1. 12:15-22. a time when behaviourally relevant neuroadaptive changes in CRF and endogenous opioid function are present [54. with relapse occurring when the sum of these motivating forces reaches a critical threshold. Ehrman R. once conditioned to drug-taking experiences. the latter emerging as an important factor in drug craving. The role of other molecular signaling mechanisms. Of relevance for this issue.13. Furthermore. and a component of NIAAA Alcohol Research Center grant AA06420. 5:9–19 . remains to be established. these authors have identified Group II mGluR-mediated glutamate transmission in the VTA as important in contextual heroin reinstatement. Robbins SJ: Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 1998. and increases in strength over prolonged abstinence. possibly involving synaptic rearrangement and altered neural excitability in the LH.92]. Similarly. In particular. drug-related environmental stimuli. The selective reversal of conditioned reinstatement by a Group II mGluR agonist (see also Update) and by N/ OFQ warrants acceleration of research devoted to these systems.14]. Data supporting the ‘allostatic’ view of www. acquire the ability to elicit craving and precipitate relapse in a manner that is resistant to extinction. Neuroadaptations previously implicated in addiction using forced drug administration regimens have been verified and extended in animals voluntarily self-administering drugs of abuse with findings of persistent perturbations in BDNF and its signaling cascades.

also diminished cocaine seeking. 161:222-232. 158:343-359. 9. Psychopharmacology (Berl) 2004. By contrast.e. Fuchs RA. Brain Res Brain Res Rev 2001. Singleton EG: Challenges in the manipulation. Miller NS. face validity). Psychopharmacology (Berl) 2003. Everitt BJ: Direct interactions between the  basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. Goeders NE. 13. 44:161-165. assessment and interpretation of craving relevant variables. a need for caution is emphasized in generalizing results from the reinstatement model to clinical conditions. Hall J. Nutt D. Unilateral infusion of a dopamine receptor antagonist into the BLA (which on its own had no effect) and concurrent application into the contralateral NAc core of an AMPA-kainate receptor antagonist (which on its own also had no effect) greatly reduced cocaine seeking. 17. Nutt DJ: Brain imaging studies in human addicts. 137:75-114. 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Selective excitotoxic lesion of the NAc core produced only minor impairments in acquisition of cocaine-reinforced responding under a schedule of continuous reinforcement. Behav Neurosci 2003. 159:1642-1652. Nat Neurosci 2004. but not the NAc core. Ito R. Robbins TW: The neuropsychological basis of addictive behaviour. Tiffany ST. Robbins TW. Psychopharmacology (Berl) 1996. Thayer JF. 36:129-138. Shalev U. and prefrontal cortex. Drummond DC: Theories of drug craving. 176:459-465. Higgins ST: The validity of the reinstatement model of  craving and relapse to drug use. Consideration of this variable provides a means by which discrepant findings among brain-imaging studies of cue-induced craving can be reconciled.e. Prog Neuropsychopharmacol Biol Psychiatry 2003. social and clinical bases of drug addiction: commentary and debate. Shaham Y. Tiffany ST: Cognitive concepts of craving. 3. Integrating neurobiological and psychological findings. resulting in motor preparation and a hyperattentive state towards drug-related stimuli that. Parker MC. This paper reviews the functional neuroimaging literature of cue-elicited craving in the context of a framework derived from behavioural data indicating that perceived drug use opportunity significantly affects responses to the presentation of drug cues. ‘functional equivalence’ in terms of resembling relapse as it occurs outside the laboratory). 19:1661-1667. but profoundly interfered with acquisition of drug-seeking maintained by cocaine-paired conditioned reinforcers under a second-order schedule contingency. 14. 168:3-20. Psychopharmacology (Berl) 2003. This doaminergic activation draws attention to the drug-related stimulus. Phillips GD. Substitution of intravenous cocaine with saline (the vehicle solution for cocaine acting as drug CS) significantly lowered brain stimulation reward thresholds.com 7. 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