The role of cAMP response element binding (CREB) protein in mediating stress induced reward and reinstatement

Exposure to stress can increase initial drug-taking as well as relapse to drug use. In this thesis, we have shown that repeated forced swim (FS) exposure prior to initial drug exposure can augment stress induced acquisition of cocaine conditioned place preference (CPP) in wild type mice. In addition, stress can precipitate previously extinguished CPP. We have further shown that an acute exposure to FS, in a context distinct from conditioning, induces reinstatement of cocaine CPP in wild type mice. To determine if this change in cocaine reward and reinstatement is dependent on CREB, we examined the behavior of mice deficient in α and Δ isoforms of CREB in these paradigms. The CREBαΔ mutant mice show deficits in FS induced enhancement as well as reinstatement of cocaine conditioned place preference. In contrast, they show robust cocaine induced reinstatement. The CRF1 receptor mediates responses to stress as well as to drugs of abuse. To investigate if changes in CRF1 receptor signaling can affect these stress induced changes in behavior in a CREB dependent manner, we examined the role of CRF1 receptor blockade in these paradigms. We find that antalarmin administration attenuates stress-induced potentiation of cocaine reward as well as FS induced reinstatement of place preference. In addition, antalarmin pretreatment blocks pCREB activation during cocaine conditioning and after FS induced reinstatement in the amygdala. This implies that the CRF1 receptor may act upstream of CREB signaling in mediating FS induced reinstatement of cocaine CPP. Together, these data reveal the common receptor signaling and molecular mechanisms underlying behavioral effects that may affect both initial drug taking as well as relapse to addiction. Exploring pharmacotherapies based on these data may provide viable options for treatment of cocaine addiction in the future