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 role for PKA–CREB signaling as a sustained “molecular switch” that gradually converts acute “drug” responses into relatively stable adaptations that contribute to drug and alcohol addiction-mediated long-lasting neural and behavioral plasticity. Under conditions of drug- and food-reinforced behavior, drug-induced reward impaired spatial discrimination learning in a Y-maze task and caused drastic decreases in pCREB and downstream target c-Fos expression in the dorsal HPC and the PFC while sparing the cued version of the task and pCREB in the dorsal striatum in mice (98). Further, pharmacological blockade of cAMP–PKA cascade into the striatum before training normalized CREB activity within the HPC–PFC circuit and, as subsequently, prevented the drug-induced modulation of multiple memory systems.
