also regulate negative emotional states induced by ethanol abstinence; for example, rolipram produces anxiolytic- and antidepressant-like effects in acute, repeated, or protracted ethanol abstinence states in rodents (Gong et al., 2017). Jabaris et al. (2015) showed that low doses of PDE-4 inhibitors increase pCREB in the rat brain, ameliorating cognitive deficits and enhancing memory, thus providing evidence for a central mechanism. PDE-4 also modulates ethanol-induced neuroinflammation. Mice chronically fed ethanol demonstrate robust activation of astrocytes, microglia, and inflammatory cytokines, as well as increased PDE4B and decreased brain cAMP. PDE4B KO or WT mice treated with rolipram are resistant to ethanol-induced brain inflammation as well as peripheral inflammation induced by systemic endotoxemia (Avila et al., 2017). Overall, there is strong preclinical evidence for PDE-4 inhibition as a potential mechanism for decreasing ethanol consumption.
