Stress-Induced Potentiation of Cocaine Reward: A Role for CRF R1 and CREB

Both clinical and preclinical research have shown that stress can potentiate drug use, however the underlying mechanisms of this interaction are unknown. Previously, we have shown that a single exposure to forced swim (FS) reinstates extinguished conditioned place preference (CPP) to cocaine and that cAMP response element binding protein (CREB) is necessary for this response. CREB can be activated by corticotropin releasing factor (CRF) receptor type 1 (CRFR1) binding, which mediates neuroendocrine and behavioral responses to stress as well as to drugs of abuse. The present experiments investigate whether changes in cocaine reward elicited by previous exposure to stress are mediated by CREB and/or CRFR1. Chronic exposure to FS in advance of conditioning enhances the acquisition of cocaine CPP in wildtype mice but this is blocked in CREB deficient mice. In addition, pretreatment with the CRFR1 antagonist, antalarmin, prior to FS exposure blocks the enhancement of stress induced acquisition of cocaine CPP. Furthermore, FS induced increase in phosphorylated CREB (pCREB), specifically in the nucleus accumbens (NAc) and the lateral septum (LS) is also blocked by antalarmin. Taken together, these studies suggest that both CREB and CRFR1 activation are necessary for stress-induced potentiation of drug reward.