NATURE NEUROSCIENCE VOLUME 8 | NUMBER 11 | NOVEMBER 2005 1437

N E U R O B I O LO G Y O F A D D I C T I O N

The role of neuroadaptations in relapse to drug seekingYavin Shaham and Bruce T Hope

One of the most difficult problems in treating addiction is not withdrawing addicts from drugs, but preventing relapse. Persistent neuroadaptations are thought to underlie aspects of addiction, including relapse. This commentary assesses the degree to which these neuroadaptations, primarily identified in preclinical studies on cocaine, induce relapse.

Relapse to drug use is one of the core features of addiction and probably the most difficult clinical problem in addiction treatment1. After prolonged abstinence, drug relapse and craving is often precipitated by acute re-exposure to the drug itself, drug-associated cues or stress2,3. This clinical scenario can be modeled in a reinstatement procedure, as stimuli that trigger human relapse also reinstate drug seek-ing in drug-abstinent animals4. In this model, mice, rats or monkeys are trained to self-admin-ister drugs by pressing a lever and then undergo ‘extinction’ training, during which lever-presses do not deliver the drug. Subsequently, the effect of ‘drug priming’ (acute noncontingent drug injections) or exposure to drug cues or stress on reinstatement of nonreinforced lever respond-ing (the operational measure of drug seeking) is measured5. The effect of drug cues on drug seeking can also be measured in extinction tests administered after different durations of absti-nence6. These extinction tests, during which rats are exposed to the drug- associated cues, permit the characterization of the time course of relapse vulnerability. The reinstatement and extinction procedures described above are regarded as valid animal models, and many investigators use these procedures to investigate the neuronal mechanisms underlying relapse to drug seeking4,7.

According to a popular hypothesis, chronic drug exposure causes long-lasting molecular, cellular and neurochemical adaptations in the brain that underlie different facets of addiction, including prolonged relapse vulnerability after cessation of drug use7–9. Here we assess the degree to which specific drug-induced neuroadaptations contribute to reinstatement of drug seeking induced by drug priming, drug cues or stress. We also discuss the role of drug-induced neuroadaptations in the progressive increase in cocaine seeking after withdrawal, a phenomenon called incubation of cocaine craving6 that was recently demonstrated in humans (T.R. Kosten, T.A. Kosten, J. Poling & A. Oliveto, College of Problems on Drug Dependence Annual Meeting Abstracts, p. 90, 2005). Our assessment suggests that although drug-induced neuroadaptations are involved in relapse to cocaine seeking, the available preclinical data do not allow us to conclude that these neuroadaptations are the main cause of long-term relapse vulnerability in humans.

Neuroadaptations and reinstatementOver a decade ago, the authors of two influential reviews10,11 hypothesized that neuroadaptations induced by repeated drug exposure that produce enduring psycho-motor sensitization also underlie drug-, cue- and stress-induced relapse to drug seeking. Sensitization refers to the enhanced psycho-motor response (quantified by measuring locomotor activity and stereotypy) that occurs after repeated exposure to psycho-stimulant or opiate drugs; this sensitized response to drugs can persist for many months after the last drug exposure10.

The neuronal systems involved in endur-ing psychostimulant and opiate sensitization are also involved in drug priming–induced reinstatement of drug seeking. The mag-nitude of drug-induced reinstatement of psychostimulant or opiate seeking is asso-ciated with sensitized drug-induced loco-motor response, and both behaviors are associated with enhanced dopamine release in the nucleus accumbens12,13. Sensitizing regi-mens of psychostimulants diminish cysteine- glutamate transporter activity, which leads to decreases in basal non-synaptic glutamate levels in the nucleus accumbens; this decrease in nonsynaptic glutamate is critical for acute cocaine-induced synaptic glutamate release7. Reversal of this neuroadaptation with systemic injections of cysteine prodrugs prevents both cocaine-induced reinstatement and cocaine-induced glutamate release14, demonstrating a link between a neuroadaptation involved in psychomotor sensitization and relapse to cocaine seeking. These and related findings led to the suggestion that pharmacotherapies for drug relapse prevention should aim at reversing cocaine-induced neuroadaptations7. A recent clinical trial based on this hypoth-esis, in which cocaine-dependent patients were treated with modafinil (a drug that increases glutamate transmission), has led to tentatively promising results15.

Several issues should be considered in evaluating the implications of the above findings for general treatment strategies. These data were derived primarily from studies using cocaine-trained rats in which drug priming provoked relapse behavior. However, drug relapse in both humans and laboratory animals is often provoked by

Yavin Shaham and Bruce T. Hope are in the

Behavioral Neuroscience Branch, Intramural

Research Program, National Institute on Drug

Abuse, National Institutes of Health, Department of

Health and Human Services, 5500 Nathan Shock

Drive, Baltimore, Maryland 21224, USA.

e-mail: yshaham@intra.nida.nih.gov

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conditions other than reexposure to the self-administered drug, including exposure to drug-associated cues1 and stress2,5,16. There is evidence that the neuronal mechanisms underlying drug seeking induced by stress, cues or drug priming are not identical16, so it is important to verify whether manipulations that reverse drug-induced neuroadaptations also prevent cue- or stress-induced rein-statement. Preliminary data suggest that this might not be the case (Z.X. Xi, J. Gilbert, A. Campos, C.R. Ashby & E.L. Gardner, Soc. Neurosci. Abstr. 691.9, 2004). Cue- or foot-shock stress–induced reinstatement was not affected by systemic injections of an antagonist of the mGluR5 metabotropic glutamate receptor, which increases basal nucleus accumbens glutamate levels and blocks cocaine-induced glutamate release and cocaine-induced reinstatement.

On the basis of studies of cross- sensitization of locomotor activity between drug and stressors11, it has been suggested that neuroadaptations associated with psy-chomotor sensitization are also involved in stress-induced reinstatement10. However, unlike drug priming, the effect of footshock stress on reinstatement is not correlated with its effect on locomotor activity and nucleus accumbens dopamine release17. These find-ings suggest that the neuroadaptations that mediate enduring psychomotor sensitization, which also potentially contribute to persis-tent drug priming–induced reinstatement (see above), are not likely to be involved in stress-induced reinstatement of drug seek-ing. A recent study, however, may be the first demonstration of cocaine-induced neuro-adaptation specific to stress-induced rein-statement18. Intermittent footshock stress increases the levels of the stress neurohor-mone corticotropin- releasing factor (CRF) in the ventral tegmental area (VTA, the cell body region of the mesolimbic dopamine reward system), and blockade of CRF receptors in this brain area attenuates stress-induced rein-statement of cocaine seeking. Furthermore, in cocaine- experienced but not in cocaine-naive rats, exposure to stress or local infusion of CRF induces glutamate release in the VTA, which in turn activates VTA dopamine neu-rons; such activation is known to induce reinstatement of drug seeking4. These data suggest that long- lasting cocaine-induced neuroadaptations in VTA neurotransmis-sion are important in stress-induced relapse to cocaine seeking. This drug-induced neu-roadaptation in CRF effects is likely to be specific to stress; CRF receptor antagonists block stress-induced but not drug priming–induced reinstatement of drug seeking17.

Neuroadaptations and incubation of cravingTo account for the persistent propensity for relapse to cocaine use, it has been suggested that craving induced by cocaine cues increases over the first several weeks of withdrawal and remains high over extended drug-free periods19. We and others identified an anal-ogous phenomenon in laboratory animals: time- dependent increases in cocaine seeking induced by exposure to cocaine cues over the first months of withdrawal (incubation of craving)20,21. We subsequently explored whether cocaine-induced neuroadaptations underlie the incubation of cocaine craving. We found that the time-dependent increase in cocaine seeking after withdrawal is asso-ciated with increasing peptide levels of the plasticity-related growth factor BDNF in the VTA, nucleus accumbens and amygdala22, and that injections of BDNF directly into the VTA increase cocaine seeking during early withdrawal23. However, sucrose-trained rats demonstrated short-term (several weeks) time-dependent increases in sucrose seeking without alterations in BDNF expression23. On the basis of these findings and other considerations, we suggested that cocaine-induced alterations of mesolimbic BDNF augment, rather than directly mediate, an ongoing incubation process6.

We also explored whether the time- dependent increase in cocaine seeking involves activation of the extracellular signal- regulated kinases (ERK) signaling pathway in the amygdala24. Cocaine activates the ERK path-way in mesolimbic dopamine areas25. In the amygdala and other brain areas, this pathway is involved in learning and memory processes26 that were hypothesized to be involved in drug addiction and relapse27,28 and may be altered by chronic exposure to abused drugs8,29. We found that exposure to cocaine cues increases ERK phosphorylation in the central, but not basolateral, amygdala after 30 d but not after 1 d of withdrawal, and that after 30 d, inhibition of central amygdala ERK phosphorylation attenuates cocaine seeking. Our data also indicate that glutamate is involved in the activation of the ERK pathway by cocaine cues. We concluded that time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues mediate the incubation of cocaine craving24. This time-dependent, sensitized response to cocaine cues may be due to cocaine-induced neuroadaptations of the central amygdala ERK pathway. Alternatively, the time- dependent increase in the amygdala ERK’s responsive-ness to cues may be a general mechanism for the incubation of craving that also occurs with non-drug rewards6.

ConclusionsThe results from the studies described above support the notion that drug-induced neuroadaptations are involved in drug relapse, as measured in preclinical models. However, this conclusion is applicable only to cocaine; the role of neuroadaptations in relapse to other abused drugs has not been assessed. Furthermore, to determine whether specific neuroadaptations are causally involved in drug relapse, experimental manipulations should aim to reverse endogenous neuroadaptations and then determine the effect of this rever-sal on relapse behavior. This experimental approach so far has been applied only to neuroadaptations’ role in cocaine priming–induced reinstatement7,14. Thus, although there is evidence that specific cocaine-induced neuroadaptations are involved in specific forms of cocaine relapse, it is too early to conclude from the available preclinical data that drug-induced brain neuroadaptations underlie long-term relapse vulnerability in humans. In this regard, given that relapse rates in humans are similar for different drugs of abuse30, it seems important to determine the generality of the findings from studies on the role of cocaine-induced neuroadaptations in relapse to other drugs. Data from studies assessing this issue of generality across drugs would also influence medication develop-ment. Most drug addicts are polydrug users1, and thus treatment approaches that involve pharmacological reversal of cocaine-induced neuroadaptations7 are more likely to succeed if neuroadaptation-related findings from studies using cocaine do generalize to other drugs. On the basis of the aforementioned similarity in relapse rates across drugs and the clinical situation of polydrug use, in our view the critical issue for future preclinical studies is the identification of specific neuroadaptations that similarly contribute to relapse in rats with a history of stimulant, opiate, alcohol and nicotine self-administration.

ACKNOWLEDGMENTSSupported by the National Institute on Drug Abuse, Intramural Research Program. We thank E. Wentzell for editorial assistance and K. Preston for helpful comments. We also would like to acknowledge L. Lu for his contribution to the work described in the section on the role of neuroadaptation in incubation of cocaine craving.

COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.

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