weiss 2005 neurobiology of craving conditioned reward and relapse

7/29/2019 Weiss 2005 Neurobiology of Craving Conditioned Reward and Relapse

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Neurobiology of craving, conditioned reward and relapseFriedbert Weiss

Chronic vulnerability to relapse is a formidable challengefor 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 ([email protected])

Current Opinion in Pharmacology 2005, 5:919

This review comes from a themed issue onNeurosciences

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

Abbreviations

BDNF brain-derived neurotrophic factorBLA basolateral amygdalaCRF corticotropin-releasing factor

CS conditioned stimuliHPA hypothalamic-pituitary-adrenalLH lateral hypothalamus

MAPK mitogen-activated protein kinasemGluR metabotropic glutamate receptorNAc nucleus accumbens

N/OFQ nociceptin/orphanin FQ

OFC orbitofrontal cortexPFC prefrontal cortexPLC prelimbic cortexVTA ventral tegmental area

IntroductionRelapse is a phenomenon pivotal for the understanding

and treatment of drug addiction. The focus of addiction

research has, therefore, shifted towards identifying theexperiential and neurobiological mechanisms responsible

for the chronically relapsing nature of addiction. Major

precipitating factors for relapse include drug craving andstress [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 drug-

induced 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 ques-tions: 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 full-

blown dependence after resumption of drug use? This

review focuses predominantly on cocaine and ethanol as

examples.

Associative learning as a factor in cravingand relapseCritical for craving and relapse is the process of associative

learning, whereby environmental stimuli repeatedly

paired with drug consumption acquire incentive-motiva-tional value, evoking expectation of drug availability and

memories of past drug euphoria [810]. 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 con-struct, craving is difficult to model with functional equiva-lence 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 ([1517]; 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

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and limbic brain regions in associative learning under-

lying craving and relapse (see Table 1). Major compo-

nents of this circuitry include the orbitofrontal cortex

(OFC), anterior cingulate, prelimbic cortex (PLC), baso-

lateral amygdala (BLA), hippocampus, nucleus accum-

bens (NAc) and, more recently, the dorsal striatum, whichis thought to participate in consolidating stimulus-

response habits via the engagement of corticostriatal

loops [10].

Substantial advances have been made in elucidating key

components and signaling mechanisms within this circui-

try that regulate specific aspects of drug-seeking using

animal models of conditioned reinforcement and condi-

tioned reinstatement (see Boxes 13). The NAc, a func-

tionally heterogeneous structure consisting of core andshell subregions (for review, see [23]), 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.

Selective inactivation of the NAc core, but not shell,

abolished cocaine CS-induced reinstatement [24], and

blockade of glutamate receptors in the NAc core elimi-

nated conditioned reinforcement by cocaine CS on a

second order schedule [25]. Moreover, functional integ-

rity of the core is required for the acquisition of condi-tioned cocaine reinforcement, whereas the shell appears

essential for the psychomotor stimulant effects of cocaine

[26]. Furthermore, the glutamatergic projection from

the BLA to the NAc core was found to be critical for the

expression of cocaine CS-maintained second order sche-dule performance [25,27]. 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]; however, in contradiction to the effects

of dopamine receptor blockade in the BLA [25], inacti-

vation of the dopaminergic projection from the VTA tothe BLA failed to interfere with the conditioned reinfor-

cing effects of cocaine CS [28]. Thus, dopaminergic

terminals in the NAc core and the BLA might differen-

tially regulate CS-maintained cocaine reinforcement

[28], the behavioural significance of which awaits clar-

ification.

In contrast to CS-maintained conditioned reinforcement

and reinstatement, recovery of extinguished drug-seek-

ing by contextual stimuli is dependent upon the NAcshell. During reinstatement evoked by a cocaine-predic-

tive contextual stimulus, neurons in the shell exhibited

significantly greater activity than those in the core, the

latter responding indiscriminately to the drug cue or

neutral stimulus [29]. Shell neuron responses to the drug

cue were still evident after four weeks of abstinence,

illustrating that the neural representation of the motiva-

tional significance of these stimuli is highly resistant to

decay [29]. Importantly, inactivation of the dorsomedial

prefrontal cortex (PFC) and BLA impaired reinstatement

by cocaine CS [30,31], whereas inactivation of the dorsal

hippocampus was selective for contextual reinstatement

[30]. However, recent data also implicate the BLA incontextual reinstatement [30,32,33] through its rostral

subdivision [34]. Thus, 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]. Overall, neural substrates for reinstatement asso-

ciated with contextual and explicit CS overlap, but also

show distinct differences.

New understanding has accrued on the function of the

OFC and PLC in drug-related learning. The OFC hasbeen found to modulate cocaine-seeking in a subregion-

specific manner, with CS-maintained reinstatement con-

trolled by the lateral OFC and drug-induced (i.e. prim-

ing) reinstatement by the medial OFC [31]. In the

PLC, rats expressing conditioned preference for a

cocaine-paired environment (i.e. a contextual stimulus)

showed increased activation of inhibitory GABAergic

interneurons, paired with decreased excitatory output

from this site [36]. The decreased activation of excitatory

PLC efferents may add to the functional defects in

prefrontal cortical regions that develop with chronic

cocaine use [3740]. Considering the executive func-tion of the PFC that includes risk-benefit analysis and

suppression of limbic impulses, the shift in activation

patterns of PLC cell populations could contribute to

impaired impulse control, and lack of judgement and

risk assessment [41], which are defining features ofaddiction.

Determinants of craving and relapse aspersistent and compulsive phenomenaClinically, a slip into limited drug use is unimportant for

ultimate therapeutic success, such that modeling craving

and reinstatement alone is not sufficient for investigatingthe chronic and compulsive nature of addiction [8]. Evi-

dence has accumulated that drug-seeking in animals

resembles along several dimensions the compulsive nat-

ure of addiction in humans. Reinstatement by drug cues is

resistant to extinction and persists over months of absti-

nence [42

,43,44

]. Even stimuli present during a singlecocaine experience elicited drug-seeking for up to one

year [45]. Importantly, the intensity of conditioned

reinstatement increases during the initial months of

abstinence [42,43,46,47]. The behavioural significanceof 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, or with-

out, presentation of drug-associated CS. Extinction

substantially decreased reinstatement (as measured by

CS-maintained responding on a second order schedule)

10 Neurosciences

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Neurobiology of craving, conditioned reward and relapse Weiss 11

Table 1

Description of the major function of brain regions covered in this review, and their role in drug addiction, craving and relapse (italicized).

Bain region Function

Prefrontal cortex Executive and decision-making functions based on the recognition of survival-related challenges, and

execution of goal-directed actions.

Orbitofrontal cortex Associative learning linked to rewarding and aversive stimuli. Integration of emotion and natural drive stateswith behaviour. Assessment of reward value against previous experience influencing action and choice

- CS-based reinstatement

- Conditioned reinforcement

- Stress-induced reinstatement

- Cue-induced craving (human functional brain imaging)

Anterior cingulate cortex Processing of pleasure and pain. Attention and cognitively demanding information processing.

Conditioned emotional learning, including attribution of emotional and motivational value to internal

and external stimuli guiding appropriate response selection.

Regulation of autonomic and endocrine function


- CS-based reinstatement

- Contextual reinstatement


Prelimbic cortex Attention, working memory, detection/evaluation of actionoutcome relationships, response initiation and inhibition.

Regulation of autonomic and endocrine function

- Conditioned reinforcement- CS-based reinstatement


- Stress-induced reinstatement

- Putative final common pathway at the cortical level for stress-, cue- and drug-induced craving and reinstatement


Basolateral amygdala Processing of emotionally significant stimuli guiding conditioned and unconditioned approach or avoidance behaviour


- CS-maintained reinstatement



Hippocampus Contextual learning and memory consolidation. Retrieval of episodic memories.

Conditioning of contextual stimuli to fear or reward


Nucleus accumbens Limbic-motor interface, integrating converging input from limbic sites related to appetitive and activational

aspects of rewards for output to effector sites, initiating and sustaining behavioural responses.

Participation in the translation of motivation into action.

NAc core - Conditioned reinforcement- CS-based reinstatement

NAc shell - Contextual reinstatement

- Molecular neuroadaptations following chronic cocaine with implications for craving and relapse


Dorsal striatum Part of the extrapyramidal motor system. Fine-tuning motoric functions.

Consolidation of stimulus-response habits via corticostriatal loops

- Presumed role in the switch from action to habit (i.e. the transition from drug abuse to drug addiction)

Ventral tegmental area Origin of the mesocorticolimbic dopamine projection

- Site implicated in Group II mGluR-mediated contextual reinstatement

- Molecular neuroadaptations following chronic cocaine with implications for craving and relapse

Lateral hypothalamus 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

- Increased in brain reward function by exposure to cocaine cues

- Impaired brain reward function associated with escalated cocaine intake

- Molecular neuroadaptations linked to escalated cocaine intakeCentral nucleus

of the amygdala

Processing of behavioural and physiological responses to stress. Key component of the extrahypothalamic

CRF stress system reciprocally connected to the BNST

Bed nucleus of the

stria terminalis (BNST)

Final common pathway processing stress and anxiety responses. Key component of the extrahypothalamic

stress system. The BNST also projects heavily to the PVN, modulating HPA axis activity

Paraventricular nucleus

of the hypothalamus

CRF-rich nucleus and apex of the HPA stress axis. CRF is the major stress-regulatory molecule in the brain

and integrates behavioural, endocrine and autonomic responses to stress

Hypothalamic-

pituitary-adrenal axis

Release of CRF from PVN neurons projecting to the anterior pituitary results in secretion of ACTH (i.e. activation

of the HPA axis) leading to secretion of adrenal glucocorticoids, predominantly corticosterone. Stress-related

addictive behaviour is thought to be related to activation of the HPA axis by CRF

- Drug cue exposure leads to HPA axis activation correlated with craving in cocaine- or

ethanol-addicted individuals

- Inteference with HPA axis activation prevents cue-induced reinstatement



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compared with one week of abstinence alone. However,

after four weeks of abstinence, CS-maintained respond-

ing in the extinguished group was increased (i.e. showed

incubation), and was identical to rats not subjected toextinction [46]. Consequently, eliminating drug avail-

ability following extinction might, with time, augment

the efficacy of drug cues to facilitate reinstatement,diminishing the effects of extinction. The time since

cessation of drug use might therefore be an important

factor in determining the efficacy of cue extinction

therapies. Drug-seekingin animals is also consistent with

defining features of addiction other than persistence.

Rats with a history of prolonged, but not limited, cocaineself-administration failed to show suppression of CS-

maintained drug-seeking when concurrently presented

with a conditioned stressor [44,49], in contrast with

the well-established inhibition of appetitive behaviour

by aversive stimuli (conditioned suppression). Thus,

drug-related cues in rats having experienced prolonged

cocaine exposure sustain drug-directed behaviourdespite adverse consequences, one of the hallmarks of

substance dependence. Rats prone to addiction on one

index of vulnerability (cocaine priming) also proved

more susceptible to other addiction-like behaviours,

including escalation of cocaine intake, conditioned rein-

statement and maintenance of cocaine-seeking despiteincreased work requirements [44]. Thus, the inflexible

dimension that characterizes addiction can readily be

demonstrated in animals but requires prolonged drug

access, confirming original findings that such exposure

regimens are critical for the transition from drug use to

dependence [50].

An important experiential factor (i.e. one related to per-

sonal experience) for the development of compulsive

drug-seeking is that consumption of a drug during

withdrawal, an event inextricably linked to addiction,

12 Neurosciences

Box 1 Animal models of craving and relapse (1): CS-based

extinction-reinstatement model.

The most widely employed method to model craving and relapse

(for review, see [19]). In this procedure, animals are trained to

respond at a lever or other operandum where completion of each

response requirement (i.e. one or more responses, 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. Each response producing a drug injection

is paired with brief (e.g. 520 s) presentation of one or more

environmental stimuli (e.g. a tone, cue light or both), referred to as

CS. Thus, both drug administration and presentation of the CS are

contingent upon a response by the animal (i.e. response-

contingent). Once reliable drug self-administration is acquired,

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.

In contemporary applications of this procedure, extinction sessions

are conducted daily until responding ceases (i.e. is substantially

lower than that maintained by delivery of the drug and deemed

incidental rather than motivated by expectation of obtaining the

drug). Subsequently, reinstatement tests are conducted in which

the degree of recovery of responding at the previously drug-pairedoperandum, now maintained by response-contingent presentation of

the conditioned CS only (i.e. without further drug delivery), is

operationally defined as a measure of craving or relapse or, more

generally, a measure of drug-seeking.

Box 2 Animal models of craving and relapse (2): second order

schedule of reinforcement.

This is another widely employed model of craving. Animals are first

trained to self-administer a drug, response-contingently paired with

presentation of a CS. Animals then are subjected to a procedure in

which only the CS is available response-contingently until

completion of a predetermined response-requirement (e.g. 2060

CS-reinforced responses), which then leads to a singleadministration of the drug reinforcer itself, whereupon the

contingency reverts again to the non-drug-reinforced schedule

component with response-contingent presentation of the CS only,

until completion of the response requirement leading to the next

drug injection. The principal measure of interest in this procedure is

the degree of conditioned reinforcement maintained by the

drug-paired CS, before drug delivery that can be operationally

defined, again, as a measure of drug craving. Although not a formal

equivalence model of relapse because of typically lacking extinction

and abstinence manipulations [14], second order schedules have

proven highly effective for investigating the significance of

conditioning factors in ongoing drug-seeking and taking (for review,

see [20]).

Box 3 Animal models of craving and relapse (3): contextual

extinction-reinstatement model.

This model is identical in most aspects to the CS-based

reinstatement model, except that it utilizes contextual stimuli (i.e.

ambient olfactory, auditory, tactile or visual stimuli in the drug

self-administration environment) for conditioning that are not

discretely paired with drug infusions nor contingent upon aresponse. Multiple contextual reinstatement procedures are

employed. The most prevalent contextual reinstatement model

utilizes cues referred to as discriminative stimuli where, during

learning, responses at the drug operandum are reinforced only in

the presence of these stimuli. Owing to their predictive nature for

drug availability, these stimuli set the occasion for engaging in

reward-seeking behavior (i.e. lead to the initiation of reponding) but

additionally, by virtue of their presence during drug consumption,

also become associated with the rewarding effects of the drug and

thus acquire incentive-motivational value (i.e. elicit memories of

previous drug euphoria and the magnitude or value of the

rewarding effect of drug consumption. Because of this dual

property, these stimuli are particularly powerful in eliciting drug-

seeking and reinstatement. Another contextual reinstatement

procedure is based on learning of a conditioned place preference

(CPP) for an environment paired with experience of the drug.Following extinction of CPP, the re-establishment (technically

termed renewal) of CPP can be operationalized to reflect a

measure of relapse and craving. Non-contingent exposure to

contextual cues readily elicits reinstatement, whereas this is not the

case with non-contingent CS presentation in CS-based

reinstatement models [21,22]. Once initiated, however, both types of

stimuli maintain responding at a previously active drug operandum

[21]. These two variants of associative learning probably occur

simultaneously during drug use but may be coded, at least in

part, through different neural circuitries or activation patterns [9].



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introduces learning about a previously latent incentive

dimension of the drug its capacity is to alleviate

physically or emotionally adverse states. This experience

can enhance the incentive value of the drug and, there-

fore, its reinforcing efficacy particularly during subse-

quent withdrawal states. Sound support for thishypothesis exists in animals [51]. This mechanism might

also be relevant for cue-induced craving and relapse,

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 drug-

related stimuli. Indeed, ethanol-dependent rats allowed

to self-administer alcohol during withdrawal, and pre-

sented with ethanol CS three weeks after withdrawal

[52], showed greater conditioned reinstatement, whereas

this was not the case in dependent rats not havingexperienced ethanol during withdrawal [53,54]. The

enhanced incentive value of drugs and associated envir-

onmental stimuli through withdrawal-related learning

could generalize to other states of aversion and negative

affect, because not only the ethanol CS but also footshock

and a conditioned stressor exacerbated reinstatement in

rats having consumed ethanol while in withdrawal, but

not in rats without this drug history [52,55]. Such general-

izations would dramatically contribute to the compulsive

nature of drug addiction.

Craving and seeking-behaviour associatedwith drug versus natural rewardsTo understand drug compulsion, we must recognize

differences that exist between the stimulus control of

behaviour motivated by natural versus drug rewards (see

chapter by Salamone et al., this issue). Prolonged expo-sure to cocaine, but not sucrose, eliminated conditioned

suppression ofreward-seeking by a footshock-predictive

cue, suggesting that the nature of the reward (drug versus

natural) determines whether compulsive behaviour

resistant to adverse environmental events develops

[44,49]. Cocaine-associated contextual stimuli elicited

reinstatement for one year, whereas the same stimulipaired with a palatable sweet solution remained effective

for only three months [45]. Conversely, incubation of

CS-induced reinstatement developed with stimuli con-

ditioned to either cocaine or sucrose [42,47]. Thus, time-

dependent variations in CS-induced reinstatement of

reward-seeking might be common to drug and naturalrewards but, by extrapolation from data above [46], could

be driven by incubation of spontaneous recovery as

an underlying process. 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. A group II metabotropic

glutamate receptor (mGluR) agonist and nociceptin/

orphanin FQ (N/OFQ), a member of the opioid peptide

family, reversed conditioned reinstatement by ethanol- or

cocaine-associated contextual cues, without altering

appetitive behaviour motivated by palatable sweet solu-

tions [56,57].

Neurobiological basis of long-lastingsusceptibility to relapse

Central to the understanding and treatment of cravingand relapse are cellular and molecular neuroadaptations

that mediate enduring associations between drugs and

associated stimuli. Increased expression of brain-derived

neurotrophic factor(BDNF) is a probable mechanism for

the incubation of conditioned reinstatement [42], a

hypothesis supported by long-lasting potentiation of

reinstatement following intra-VTA application of BDNF

[58]. The role of BDNF in reinstatement appears to

depend critically upon recruitment of mitogen-activated

protein kinase (MAPK) signal transduction [58], a path-way involved in long-term potentiation and synaptic

plasticity, processes that have been implicated in devel-

opment of addiction [59,60]. 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, as

well as transient elevation of cyclin-dependent protein

kinase 5 in the VTA [61]. Increased BNDF expression

initiates a plethora of signaling cascades with implica-

tions for addiction (for review, see [62]), including

changes in synaptic strength, neural signaling and den-

drite formation. Repeated cocaine increases dendriticsprouting in the NAC, PFC and caudate-putamen that

persists for months [6365] structural changes with a

presumptive role in sensitization and the persistence of

craving and relapse risk. The activation of cyclin-depen-

dent protein kinase 5, also linked to proliferation ofdendritic sprouting [66], might be a contributing factor.

Chronic cocaine (or morphine) also alters postreceptor

signaling cascades for BDNF in the meso-accumbens

pathway, one of which sustains MAPK activation during

prolonged cocaine abstinence [62]. Pharmacological

interference with MAPK signaling reduces preference

for a cocaine-paired environment [67], thus supportingthe 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. Molecular neuro-

adaptations in two other regulatory systems are also of

interest. The first cocaine-induced alteration incystine-glutamate exchange in the NAc regulates

basal extracellular glutamate levels, resulting in reduced

levels of this amino acid during cocaine withdrawal, an

effect implicated in susceptibility to relapse [68]. Thesecond upregulation of an activator of G protein

signaling showed significant elevation in the PFC

and NAc after only one week of cocaine exposure, and

was still evident after two months of abstinence [69].

Although a behavioural function for these neuroadapta-

tions has been demonstrated only for cocaine-induced

reinstatement, these molecular changes are promising




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targets to explore with respect to a role in cue-elicited

craving and relapse.

Finally, an emerging neuropharmacological mechanism

in craving and relapse is the endocannabinoid system that

functionally interacts with numerous other brain neuro-transmitter systems with established roles in drug-seek-

ing and addiction [70]. The endocannabinoid system has

been implicated in opiate, cocaine and alcohol addition

[71,72]. More importantly, pharmacological manipulation

of this system modifies both heroin reinforcement and

conditioned reinstatement [73].

Different neurocircuitries for drug versusnatural reward?Conditioned responses, whether motivated by drugs ofabuse or natural rewards, are thought to be processed via

the same neurocircuitry [18,74,75]. It is unclear, however,

what differentiates neural signaling regulating normal

appetitive behaviour versus pathological behaviour

resulting from drug-related conditioning. NAc neurons,

activated during cocaine-reinforced responding, were also

responsive to cocaine CS, whereas cell populations acti-

vated only by water reinforcement were not (reviewed in

[76]). 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) butwith stronger effects evoked by drug cues [77]. Brain

regions activated by drug cues, therefore, might not be

specific to addiction-related events but components of

normal circuits activated to a greater degree, and may

reflect either the creation of new motivational states suchas those produced by withdrawal-related learning [74] or

the tilting of processes that normally govern responding

for natural rewards towards drug-directed behaviour.

Differential activation of BDNF-induced signaling might

be a contributory factor, as increased BDNF expression is

linked to incubation of conditioned cocaine- but not

sucrose-seeking behaviour [42].

Dysregulation of hedonic homeostasisA widely held position in addiction theory views craving

and relapse as an opponent motivational process to avoid

negative affect (e.g. dysphoria, anhedonia and anxiety),

which is a consequence of withdrawal from most drugs ofabuse. The most recent conceptualization of this process

focuses on the development of allostasis, defined as a

state of progressive deviation of motivational regulatory

systems by chronic drug use from their normal function,with the establishment of a new hedonic set point (for

review, see [50,78]). 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 hedo-

nic impact of cocaine [79]. Allostasis has also been linked

to dysregulation in molecular signaling systems. Tran-

scriptional profiling by DNA microarray revealed that

escalated cocaine intake is associated with alterations in

transcripts relevant for neurite extension and synaptogen-

esis, cell adhesion and nerve regeneration, as well as for

neuronal excitability and glutamate transmission (cited as

unpublished in [50]). Increases in ionotropic and mGluRsubunits during withdrawal support such changes in glu-

tamate transmission during prolonged cocaine exposure

[80]. Interestingly, gene transcript changes in cocaine

escalated rats were confined largely to the lateral hypotha-

lamus(LH); therefore, synaptic rearrangement and altered

neural excitability in the LH could play a role in compul-

sive cocaine-seeking [50] (for related discussion, see [81]).

Stress as a source of cravingStress, although complex and influenced by multiplefactors, has an established role in relapse [2]. Footshock

(as a model of stress) reinstates extinguished responding

previously maintained by drugs of abuse. Several theore-

tical views exist on the motivational mechanisms by

which stress provokes relapse as discussed in several

excellent reviews [82,83,84]. Of interest here is the

growing evidence that drug cue and stress manipulations

induce a similar pattern of craving and cue reactivity,

including comparable increases in negative affect and

anxiety [85,86], findings that support the allostatic view

of addiction. Exposure to drug cues in cocaine-dependent

subjects produced increases in both craving and corti-cotropin-releasing factor/hypothalamic-pituitary-adrenal

(CRF/HPA)-axis-dependent behavioural and physiologi-

cal measures of stress [86]. Consistent with these find-

ings, corticosterone synthesis inhibition and blockade of

CRF1 receptors in rats attenuated cocaine CS-inducedreinstatement (i.e. a measure ofcraving), indicative of a

role for stress (i.e. HPA axis activation) in the response-

reinstating actions of drug cues [22]. These observations

implicate overlap between neural substrates controlling

craving evoked by drug cues and stress. Stress, via HPA

axis activation, increases mesocorticolimbic dopamine

transmission. Both aversive and appetitive events areprocessed by interactions among limbic subcortical and

prefrontal cortical regions, including the BLA and OFC,

with ultimate effects on extrahypothalamic and neuroen-

docrine stress responses through direct and indirect con-

nections with the bed nucleus of the stria terminalis,

central nucleus of the amygdala, and hypothalamic para-ventricular nucleus (reviewed in [2]). Thus, activation of

both brain motivational circuits and stress-regulatory sys-

tems by drug cues and stress implicates common neural

substrates through which these challenges enhance drug-

seeking. Transient lesion and site-specific pharmacologi-

cal manipulation of PFC regions have implicated the

PLC and OFC as components of a circuitry mediating

footshock-induced drug-seeking, with the PLC repre-

senting a possible common pathway for stress-, cue-

and drug-induced reinstatement [87]. Lastly, evidence

for overlap between the neural substrates mediating stress

14 Neurosciences



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and drug cue effects exists also at the pharmacological

level. Several agents that attenuate conditioned reinstate-

ment [56,57] alsohave marked anti-stress and anxiolytic

profiles. These include Group II mGluR agonists [8890]

and N/OFQ, which exerts strong CRF antagonist actions in

the bed nucleus of the stria terminalis [91].

Interactions among risk factors for cravingand relapseAlthough craving and stress are undoubtedly important

for relapse, a predictive relationship between subjective

reports of stress or craving and subsequent drug use is a

matter of some dispute [2,12,13,14]. Risk factors for

relapse are typically studied in isolation, whereas absti-

nent drug users are frequently exposed to multiple exter-

nal risk factors, while experiencing varying degrees ofprotracted withdrawal symptoms. Of relevance for this

issue, reinstatement of alcohol-seeking was found mark-

edly enhanced when rats were subjected to footshock

stress before response-contingent exposure to ethanol CS

[52,55]. 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, a time when behaviourally relevant

neuroadaptive changes in CRF and endogenous opioid

function are present [54,92]. 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,with relapse occurring when the sum of these motivating

forces reaches a critical threshold. Systematic investiga-

tion of such interactions could substantially advance

current understanding of the relapse process.

ConclusionsThe past three years have seen major advances in under-

standing of the experiential and neurobiological basis of

craving and vulnerability to relapse. Behaviourally, pro-

longed exposure to drugs of abuse in animals has con-

sequences consistent with defining features of substance

dependence in humans, providing crucial support for theutility of animal models as tools for investigating the

neural basis of specific aspects of addiction. In particular,

drug-related environmental stimuli, once conditioned to

drug-taking experiences, acquire the ability to elicit crav-

ing and precipitate relapse in a manner that is resistant to

extinction, impervious to punishment, and increases instrength over prolonged abstinence. Novel data indicate

strong overlap between neural substrates controlling drug

desire evoked by drug cues and stress, the latter emerging

as an important factor in drug craving. 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, as well as in glutamate receptor sub-

units and gene transcripts linked to regulation of excitatory

neurotransmission. Data supporting the allostatic view of

craving and relapse show that repeated withdrawal from

escalated cocaine intake leads to long-lasting deficits in

brain reward function, possibly involving synaptic rearran-

gement and altered neural excitability in the LH.

Clearly, major gaps remain in our knowledge of thecontrol of craving and relapse. For example, only the

time profile of BDNF corresponded well with incubation

of drug-seeking. The role of other molecular signaling

mechanisms, both in incubation and vulnerability to

relapse in general, remains to be established. Similarly,

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.

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, both with regard to a mechanistic role in addic-

tion and as drug targets for relapse prevention. Further-

more, the important function postulated for the dorsal

striatum in consolidating addiction-related stimulus-

response habits would benefit from confirmation as to

whether this role applies specifically to ongoing drug-

seeking maintained by conditioned reinforcers or also to

relapse. This question is important because inactivation

of the dorsolateral striatum failed to interfere with con-

ditioned reinstatement of cocaine-seeking following

extinction and abstinence [93]. Lastly, investigation ofhow interactions among risk factors exacerbate the like-

lihood of resumption of drug use could substantially

advance our current understanding of the relapse process.

UpdateRecent work has confirmed that Group II mGLuR acti-

vation by the mGlu2/3 agonist LY379268 attenuates

context-induced reinstatement of heroin-seeking [94].

Moreover, these authors have identified Group II

mGluR-mediated glutamate transmission in the VTA

as important in contextual heroin reinstatement. Impor-

tantly, these results also verified the selectivity of Group

II mGluR activation for drug-seeking behavior, as

LY379268 had no effect on responding for oral sucrose.

AcknowledgementsThe author acknowledges National Institutes of Health fundingthrough National Institute on Drug Abuse grants DA07348, DA08467

and DA017097; National Institute on Alcohol Abuse and Alcoholism(NIAAA) grants AA10531 and AA014351; and a component of NIAAAAlcohol Research Center grant AA06420. The author would like to thankMike Arends for his editorial assistance.

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of special interest

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80. TangW, WesleyM, Freeman WM,LiangB, Hemby SE:Alterationsin ionotropic glutamate receptor subunits during bingecocaine self-administration and withdrawal in rats.J Neurochem 2004, 89:1021-1033.

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An elaborate study that scrutinizes the response of brain stress circuits incocaine-dependent subjects exposed to guided imagery proceduresknown to increase cocaine craving. Stress and drug imagery manipula-tions each produced significant increases in craving and subjectiveanxiety, pulse rate, systolic blood pressure and levels of adrenocortico-tropic hormone, cortisol, prolactin and norepinephrine, compared withneutral imagery. Of interest, these data confirm not only that similarcraving states are elicited by stress and drug cue exposure, but alsothat the neurobiological basis of these reactions is shared with a sig-nificant activation of the CRF/HPA axis and noradrenergic/sympatho-adreno-medullary system response.

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This paper addresses the issue of common neural substrates for cocainecraving associated with different risk factors, with a focus on the role ofthe PFC in cocaine-seeking induced by footshock stress and priminginjections. Based on the effects of transient tetrodotoxin lesions, site-specific pharmacological manipulations and findings in related literature,a picture emerges that implicates thePLC andOFC as part of thecircuitryspecifically mediating the effects of footshock stress on reinstatement.The PLC is proposed as a possible common pathway for cue, foot-shock

and cocaine-induced reinstatement of drug seeking.

88. Scaccianoce S, Matrisciano F, Del Bianco P, Caricasole A,Di Giorgi Gerevini V, Cappuccio I, Melchiorri D, Battaglia G,Nicoletti F: Endogenous activation of group-II metabotropicglutamate receptors inhibits the hypothalamic-pituitary-adrenocortical axis. Neuropharmacology 2003, 44:555-561.

89. Linden AM, Greene SJ, Bergeron M, Schoepp DD: Anxiolyticactivity of the mGlu2/3 receptor agonist LY354740 on theelevated plus maze is associated with the suppression ofstress-induced c-Fos in the hippocampus and increases inc-Fos induction in several other stress-sensitive brainregions. Neuropsychopharmacology2004, 29:502-513.

90. Swanson CJ, Perry KW, Schoepp DD: The mGlu2/3 receptoragonist, LY354740, blocks immobilization-induced increasesin noradrenaline and dopamine release in the rat medialprefrontal cortex. J Neurochem 2004, 88:194-202.

91. Ciccocioppo R, Fedeli A, Economidou D, Policani F, Weiss F,Massi M: The bed nucleus is a neuroanatomical substrate forthe anorectic effect of corticotropin-releasing factor and forits reversal by nociceptin/orphanin FQ. J Neurosci 2003,23:9445-9451.

92. Valdez GR, Zorrilla EP, Roberts AJ, Koob GF: Antagonism ofcorticotropin-releasing factor attenuates the enhancedresponsiveness to stress observed during protracted ethanolabstinence. Alcohol 2003, 29:55-60.

93. Kantak KM, Black Y, Valencia E, Green-Jordan K,Eichenbaum HB: Stimulus-response functions of the lateraldorsal striatum and regulation of behavior studied in acocaine maintenance/cue reinstatement model in rats.Psychopharmacology (Berl) 2002, 161:278-287.

94. Bossert JM, Liu SY, Lu L, Shaham Y: A role of ventral tegmentalarea glutamate in contextual cue-induced relapse to heroinseeking. J Neurosci 2004, 24:in press.



weiss 2005 neurobiology of craving conditioned reward and relapse

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