Recent clinical studies, including those of the Center, have shown that psychological stressors elevate drugcraving and hypothalamic-pituitary-adrenal (HPA) axis activity, and that stress-induced HPA axis responsespredict amounts of subsequent drug use. The hypothesis of this Project is: withdrawal from drugs of abuseand exposure to stress persistently alter gene expression levels of HPA axis and brain stress responsivesystems in rodent extended amygdalar and mesocorticolimbic regions; critically contributing to persistentcompulsive drug taking and relapse of drug seeking. During the current funding period, it has been foundthat a) arginine vasopressin (AVP) gene expression in the medial amygdala is activated during earlywithdrawal from heroin; and b) a selective AVP V1b receptor antagonist attenuates both reinstatement ofheroin-seeking behaviors and HPA activation induced by stress in long-term heroin withdrawal. Thissuggests that amygdalar AVP/V1b receptor and HPA systems are critical components of the neural circuitryunderlying the aversive emotional consequences of drug withdrawal, and the effect of negative emotionalstates on drug seeking behavior (negative reinforcing mechanism). Increases in AVP gene expression in theamygdala are further found in acute cocaine withdrawal, and are mediated via opioid receptor activation.Therefore, the first goal of this project is to determine the role of the AVP/V1b receptor systems in relapse tococaine seeking and taking behaviors (Aim 1). The other main goals of this project are to characterizespecific stress responsive genes with respect to: (a) dynamic and region-specific alterations after long-termwithdrawal from chronic drug exposure after acute and chronic drug re-exposure (Aim 2) or after acute stress(Aim 3); (b) their correlations with stress-induced anxiety- or depression-like behaviors (Aim 3); (c) theircorrelations with stress-induced drug seeking or taking behaviors (Aim 1); and (d) potential epigeneticmechanisms underlying alterations of gene expression (Aim 4). The focus of this proposol is to study acuteand chronic drug re-exposure after long-term withdrawal. The results will elucidate essential mechanisms forstress and opioid systems in the regulation of drug addictive-like states, which may lead to the identificationof potentially novel therapeutic targets.
Showing the most recent 10 out of 168 publications
