Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens

Drugs of abuse regulate the transcription factor cAMP response element-bind ing protein (CREB) in striatal regions, including the nucleus accumbens (NA c). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this regio n or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CRE B function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased co caine reward. Conversely, rats treated with HSV-CREB spent less time in coc aine-associated environments, indicating increased cocaine aversion. Studie s in which drug-environment pairings were varied to coincide with either th e early or late effects of cocaine suggest that CREB-associated place avers ions reflect increased cocaine withdrawal. Because cocaine withdrawal can b e accompanied by symptoms of depression, we examined how altered CREB funct ion in the NAc affects behavior in the forced swim test (FST). Elevated CRE B expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link betw een CREB and dysphoria. Conversely, overexpression of mCREB decreased immob ility, an effect similar to that caused by antidepressants. Moreover, the k appa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induct ion of dynorphin (an endogenous kappa receptor ligand) contributes to immob ility behavior in the FST Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-m ediated transcription within the NAc regulates dysphoric states.