Chronic rolipram treatment also results in sustained reduction of alcohol seeking and consumption in alcohol-preferring rats (95, 96). As mentioned earlier, mice subjected to 1- or 6-week alcohol withdrawal from chronic alcohol consumption exhibited working memory impairments accompanied by enhanced anxiety level (at 1 week only) as well as persistently elevated corticosterone and sustained decreased pCREB levels in the PFC. Intraperitoneal administration of the PDE4 inhibitor, rolipram, before working memory testing abolished these withdrawal-associated behavioral, endocrine, and neuronal alterations (31) – a finding consistent with other observation, which demonstrated that in rats, heightened anxiety during acute alcohol withdrawal was accompanied by elevated expression of Pde10a isoform mRNA levels in interconnected medial PFC–AMG circuit, which persisted in the AMG after protracted (6 weeks) alcohol withdrawal (97). Together, these observations strongly support further research with regard to isoform-specific PDE-selective inhibitors that are promising pharmacotherapy targets for alcohol use disorders.
