T H E   N I H   C A T A L Y S T     S E P T E M B E R  –  O C T O B E R   2003




Yavin Shaham

Yavin Shaham received his M.A. in 1988 from the Hebrew University, Jerusalem, and his Ph.D. in 1992 from the Uniformed Services University of the Health Sciences, Bethesda. His postdoctoral training from 1992 to 1995 was at Concordia University, Montreal, in the laboratory of Jane Stewart. Subsequently, he was an affiliated scientist at the Addiction Research Center, Toronto, and an assistant professor in the Psychology Department at the University of Toronto. He joined NIDA in 1998 as a tenure-track investigator, and he is currently the chief of the Neurobiology of Relapse Section of the Behavioral Neuroscience Branch.

In the Neurobiology of Relapse Section,* we use a rat model to study neuronal mechanisms that may underlie relapse to heroin, cocaine, and methamphetamine seeking induced by stressors and drug-associated cues. In the rat relapse model, we measure resumption of lever-pressing behavior induced by drug or nondrug stimuli, following training for intravenous drug self-administration and subsequent extinction of the drug-taking behavior. Our main projects are described below.

Stress-induced relapse. Human studies report that stress increases relapse to drug use, but until recently there has been no animal model to study the mechanisms mediating this effect. During my postdoctoral training, Jane Stewart and I developed a rat model to study the effect of stress on relapse in rats. We found that exposure to mild intermittent footshock, a common stressor in animal studies, reliably reinstates heroin seeking after prolonged withdrawal periods.(1)

Subsequently, we and others found that this effect extends to other drugs of abuse (cocaine, nicotine, alcohol) and to certain other stressors.(2) We also identified two brain neurotransmitters—corticotropin-releasing factor (CRF) and noradrenaline—and two brain sites—the central nucleus of the amygdala and the bed nucleus of stria terminalis—that play major roles in stress-induced relapse.(3, 4)

Over the last several years, our research has been extended to successful human studies on the effect of stress on drug craving. Also, two drug classes found effective in our rat studies are either in clinical trials for relapse prevention (a-2 adrenoceptor agonists) or in planning phases for such trials (CRF1 receptor antagonists).

Incubation of cue-induced cocaine seeking. Cocaine addiction is characterized by high relapse rates after prolonged withdrawal periods. Gawin and Kleber hypothesized that human addicts become progressively more sensitive, over the first months of withdrawal from cocaine, to drug-associated cues. Experimental evidence for this hypothesis, however, was not available.

We developed a rat model to study the effect of the cocaine withdrawal period on cue-controlled drug seeking. We found a progressive enhancement, over two months of withdrawal from cocaine, of lever-pressing behavior after exposure to cocaine cues.(5) These data suggest that the individual is most vulnerable to relapse provoked by drug cues at time points that are well beyond the acute withdrawal phase.

In a collaborative study with Tsung-Ping Su and Teruo Hayashi from our institute, we found that the time-dependent changes in cue-induced drug seeking over the first 90 days of withdrawal are associated with alterations in brain-derived neurotrophic factor within components of the mesolimbic dopamine reward system.(6)

In another collaborative study with Bruce Hope from our branch, we also found that in the brains of cocaine-experienced rats, glutamate receptors in regions of the mesolimbic dopamine systems are upregulated for up to 90 days after drug withdrawal.(7)

We and several other laboratories are exploring further the neuronal mechanisms involved in the new phenomenon of incubation of cue-controlled cocaine seeking after withdrawal.

The drug environment and relapse to heroin and cocaine. In humans, environmental stimuli associated with drug intake play an important role in drug relapse. These stimuli can be divided broadly into two categories: 1) discrete drug cues (such as a needle or white powder) that are temporally associated with the acute rewarding effects of the drug and 2) contextual drug cues (such as a specific bar) that can become predictors of drug availability, but are not temporally associated with the acute rewarding effects of the drug.

Many laboratories currently explore the neuronal events underlying the effect of discrete cues on relapse. In contrast, little is known about the mechanisms mediating drug context-induced relapse.

We recently adapted a rat model (originally developed by Bouton and Bolles in fear-conditioning studies) to study the effect of the drug context on relapse. We found that in rats trained to self-administer speedball (a mixture of heroin and cocaine), re-exposure to the drug-taking context reinstates drug seeking after extinction of the self-administration behavior in a different context.(8)

We are currently exploring neurotransmitters and brain sites involved in context-induced reinstatement of drug-seeking.


1. Y. Shaham, J. Stewart, "Stress reinstates heroin self-administration behavior in drug-free animals: an effect mimicking heroin, not withdrawal," Psychopharmacology 119: 334–341, 1995.

2. Y. Shaham, U. Shalev, L. Lu, H. de Wit, J. Stewart, "The reinstatement model of drug relapse: history, methodology and major findings," Psychopharmacology 168:3–20, 2003.

3. Y. Shaham, S. Erb, J. Stewart, "Stress-induced relapse to heroin and cocaine seeking in rats: a review," Brain Res. Rev. 33:13–33, 2000.

4. U. Shalev, J.W. Grimm, Y. Shaham, "Neurobiology of relapse to heroin and cocaine: a review," Pharmacol. Rev. 54:1–42, 2002.

5. J.W. Grimm, B.T. Hope, R.A. Wise, Y. Shaham, "Incubation of cocaine craving after withdrawal," Nature 412:141–142, 2001.

6. J.W. Grimm, L. Lu, T. Hayashi, B. T. Hope, T.P. Su, Y. Shaham, "Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving," J. Neurosci. 23:742–747, 2003.

7. L. Lu, J.W. Grimm, Y. Shaham, B.T. Hope, ´Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats,ª J. Neurochem. 85:1604–1613, 2003.

8. H.S. Crombag, Y. Shaham, "Renewal of drug seeking by contextual cues after prolonged extinction in rats," Behav. Neurosci. 116:169–173, 2002.

The section currently comprises two visiting fellows, Lin Lu and Jennifer Bossert, and two students, Jack Dempsey and Shirley Liu, whose hard work and dedication are gratefully acknowledged.



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