Disruption of Phosphodiesterase-4 (PDE4) Subtypes to Reduce Ethanol Consumption

Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in regulating alcohol consumption. Our previous studies showed that inhibitors of phosphodiesterase-4 (PDE4) increased cAMP in the brain and decreased ethanol intake in the two-bottle choice test in mice. However, since there are no selective inhibitors of individual PDE4 subtypes (PDE4A-D), it is not known which PDE4 subtype(s) is (are) involved. Using mice deficient in PDE4A, PDE4B, or PDE4D, the major PDE4 subtypes in the brain, we determined the contributions of individual PDE4 subtypes to ethanol intake and preference. Mice deficient in either PDE4A or PDE4B displayed decreases in ethanol (7–12%) intake and ethanol preference by more than 50% relative to wild-type controls in the two-bottle choice test. They also exhibited decreases in ethanol intake in the ethanol (9%) drinking-in-the-dark paradigm. In contrast, mice deficient in PDE4D showed only slight decreases in ethanol consumption. Sucrose (2% and 4%) intake was also decreased in mice deficient in PDE4A or PDE4B relative to WT controls, but quinine intake was not changed between the genotypes. Therefore, both PDE4A and PDE4B appear to be important PDE4 subtypes in the regulation of ethanol consumption. Selective inhibitors of PDE4A or PDE4B may be used for treatment of alcohol dependence.