Behavioral Neuroscience Research Branch
Neurobiology of Relapse Section
Overview
We use rat models to study the cellular and neuroanatomical mechanisms that underlie relapse to drug and palatable food seeking induced by stressors and drug-associated cues (Shaham group). We also examine molecular, cellular, and electrophysiological mechanisms that mediate the learning of associations between drugs and the environment in which they are administered (Hope group).
Areas of Research and Future Directions
Shaham Group
Stress-induced relapse
In 1994, we developed a rat model to study the effect of stress on relapse to drug seeking. We found that exposure to intermittent footshock stress and several other stressors reinstates drug seeking after prolonged withdrawal periods. Over the last 10 years, we and others have identified several brain sites and neurotransmitters that are involved in stress-induced relapse (for reviews see Shaham et al. Brain Res. Rev. 2000; Shalev et al. Pharmacol. Rev. 2002). Additionally, two drug classes found effective in our rat studies are now either in clinical trials for relapse prevention (alpha-2 adrenoceptor agonists) or in planning phases for such trials (CRF1 receptor antagonists). Currently, we are working to characterize the brain mechanisms underlying the potent effect on reinstatement of yohimbine (Shepard et al. Biol. Psychiatry, 2004), an alpha-2 adrenoceptor antagonist that induces stress-like symptoms in humans. We perform these studies primarily on rats that are trained to lever press for palatable food pellets.
Incubation of cocaine craving
In this project, we study the effect of the duration of the cocaine withdrawal period on cue-induced drug seeking. In our initial study, we found a progressive increase in rats’ responsiveness to cocaine cues over the first months of withdrawal, a phenomenon we termed incubation of cocaine craving (Grimm et al. Nature, 2001). We recently characterized the role of mesolimbic BDNF in the persistent responsiveness to cocaine cues after withdrawal (Grimm et al. J. Neurosci. 2003; Lu et al. J. Neurosci. 2004). We also investigated the role of amygdala ERK signaling pathway and glutamate in the incubation of cocaine craving (Lu et al. Nat. Neurosci. 2005). We currently continue to explore the cellular and neuroanatomical mechanisms underlying the incubation of cocaine craving, as measured in our rat model.
The drug environment and relapse to heroin and cocaine
We recently adapted a “renewal” model (originally developed in fear conditioning studies in rats) to study the effect of the drug-associated context on relapse to drug seeking. We found that in rats trained to self-administer heroin, cocaine, or speedball (a heroin-cocaine combination), re-exposure to the drug-taking context reinstates drug seeking after extinction of the self-administration behavior in a different context (Crombag & Shaham, Behav. Neurosci. 2002; Crombag et al. Neuropsychopharmacology, 2002). We currently study the role of mGluR2/3 receptors in mesolimbic sites such as the ventral tegmental area (Bossert et al. J. Neurosci. 2004) and the nucleus accumbens in context-induced reinstatement of heroin seeking.
Hope Group
Molecular and cellular alterations that mediate drug-associated learning
Animals learn to associate the effects of a drug with the environment where the drug is administered. We examine altered reactivity of neurons in the nucleus accumbens after repeated administration of cocaine or amphetamine in a novel environment. By assessing induction and activation of various intracellular signaling proteins (Fos, CREB, ERK), we found that repeated drug administration produces enhanced cellular responding in the nucleus accumbens that persists for up to 6 months and is dependent on the administration of the drug in the same environment that was previously associated with cocaine. Thus, after repeated exposure to cocaine, a specific set of nucleus accumbens neurons is selected by the environment to be activated by the drug and these neurons are likely involved in the learned associations between drug effects and the environment. We currently use a transgenic rat model to identify and characterize these neurons in electrophysiological slice preparations; we also use this rat model to selectively lesion these specific neurons in behaving animals in order to examine their roles in drug-related behaviors.
Personnel
Investigators
Yavin Shaham
Bruce Hope
Post-doctoral fellows and visiting scientists
Lin Lu
Jennifer Bossert
Udi Ghitza
Sunila Nair
Eisuke Koya
Post-baccalaureate students
Sarah Gray
Gabriela Poles
Jamie Uejima
Timothy Mitchell
Selective Recent Publications
Empirical Papers
Shaham Group
Shalev U, Yap J, Shaham Y (2001) Leptin attenuates food deprivation-induced relapse to heroin seeking. The Journal of Neuroscience 21: RC129:1-5
Grimm JW, Hope B, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141-142
De Vries T, Shaham Y, Homberg J, Schuurman K, Crombag H, Vanderschuren LJMJ, Schoffelmeer ANM (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nature Medicine 7: 1151-1154
Lê AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. The Journal of Neuroscience 22:7844-7849
Grimm JW, Lu L, Hayashi T, Su TP, Hope BT, Shaham Y (2003) Time dependent increases in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system following withdrawal from cocaine: implications for incubation of cocaine craving. The Journal of Neuroscience 23:742-747
Lu L, Dempsey J, Liu S, Bossert J, Shaham Y (2004) A single infusion of BDNF into the ventral tegmental area induces long-lasting potentiation of cocaine-seeking after withdrawal. The Journal of Neuroscience 24:1604-1611
Bossert JM, Liu S, Lu L, Shaham Y (2004) A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. The Journal of Neuroscience 24: 10726-10730
Lu L, Hope BT, Dempsey J, Liu S, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nature Neuroscience 8:212-219
Hope group
Morón JA, Brockington A, Wise R, Rocha BA, Hope BT (2002) Dopamine uptake through the NET in brain regions with low levels of the DAT: Evidence from knockout mouse lines. The Journal of Neuroscience 22:389-395
Jedynak JP, Ali SF, Haycock JW, Hope BT (2002) Acute administration of cocaine regulates the phosphorylation of serine-19, -31, and -40 in tyrosine hydroxylase. Journal of Neurochemistry 82:382-388
Lu L, Grimm JW, Shaham Y, Hope BT (2003) Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. Journal of Neurochemistry 85:1604-1613
Hope BT, Crombag HS, Jedynak JP, Wise RA (2005) Neuroadaptations in total levels of adenylate cyclase, protein kinase A, tyrosine hydroxylase, cdk5, and neurofilaments in the nucleus accumbens and ventral tegmental area do not correlate with expression of sensitized or tolerant locomotor responses to cocaine. Journal of Neurochemistry 92:536-545
Lu L, Dempsey J, Shaham Y, Hope BT (2005) Differential long-term neuroadaptations of glutamate receptors in the basolateral and central amygdala after withdrawal from cocaine self-administration in rats. Journal of Neurochemistry 94:161-168
Mattson BJ, Bossert JM, Simmons DE, Nozaki N, Nagarkar D, Kreuter JD, Hope BT. (2005) Cocaine-induced CREB phosphorylation in nucleus accumbens of cocaine-sensitized rats is enabled by enhanced activation of ERK, but not PKA. Journal of Neurochemistry (in press)
Reviews and commentaries
Shaham Y, Erb S, Stewart J (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Research Reviews 33:13-33
Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacological Reviews 53: 209-244
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine: a review. Pharmacological Reviews 54:1-42
Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3-20
Lu L, Hope BT, Shaham Y (2004) The cystine–glutamate transporter in the accumbens: a novel role in cocaine relapse. Trends in Neuroscience 27:74-76
Lu L, Shepard J, Hall SF, Shaham Y (2003) Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neuroscience and Biobehavioral Reviews 27:457-491
Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(S1): 214-227 (invited review for a special issue commemorating 30 years of NIDA research)
Bossert JM, Ghitza U, Lu L, Epstein DE, Shaham Y (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. European Journal of Pharmacology (in press)
Shaham Y, Hope BT (2005) The role of neuroadaptations in relapse to drug seeking. Nature Neuroscience (invited commentary for a special issue on the Neurobiology of Addiction)
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Behavioral Neuroscience Research Branch
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