As discussed above, long-term adaptive behavioral effects of chronic alcohol exposure are mediated in large part through long-lasting glucocorticoid dysregulation within the PFC but not the dorsal HPC. Confirming differential sensitivity of the PFC and dorsal HPC to chronic alcohol-induced damage, recent work in our laboratory has shown that, unlike the PFC in which withdrawal from prolonged alcohol intake caused persistent working memory impairments along with sustained inhibition of the cAMP–PKA–CREB signaling cascade, both alcohol (unimpaired) and alcohol withdrawal (impaired) mice display reduced levels of pCREB in the dorsal HPC (namely, the CA1 region), compared with water-drinking mice (31, 47). Furthermore, intraperitoneal administration of rolipram was able to correct the deficit in pCREB in the dorsal HPC but did not reverse working memory impairments in withdrawn animals (47). Together, these observations support the notion that disruption of the cAMP–PKA–CREB signaling cascade specifically in the PFC (but not in the dorsal HPC) has an essential role in promoting long-term neuroadaptive changes accompanying persistent behavioral changes during withdrawal from chronic alcohol intake. Interestingly, early pioneering work in our laboratory emphasized a key
