Role of phosphodiesterase‐4 (PDE4) in alcohol‐ and heroinseeking behavior

Abstract

Cyclic AMP (cAMP) signaling is important in mediating drug abuse and dependence, including alcoholism. As a critical controller of intracellular cAMP levels in the brain, phosphodiesterase‐4 (PDE4), an enzyme that specifically hydrolyzes cAMP, may play a role in drug dependence. Here we examined the effects of rolipram, a selective PDE4 inhibitor, on alcohol or heroin seeking behavior in mice and/or rats. Treatment with rolipram (0.1–0.5 mg/kg) decreased ethanol (7–12%) intake and preference in high alcohol preferring mice and rats in two‐bottle choice and/or ethanol drink‐in‐dark tests. Deficiency of PDE4B diminished rolipram‐induced decreases in ethanol consumption in mice. In addition, rolipram (0.025–0.05) also decreased ethanol responses in operant self‐administration in rats. Further, in heroin self‐administration, rolipram (0.03–0.3 mg/kg) decreased cues‐ or heroin priming‐induced responses, but did not alter responses to heroin injections. These results suggest that PDE4 plays an important role in the regulation of ethanol‐ and heroin‐seeking behaviors, which are attenuated by PDE4 inhibitors such as rolipram. Targeting PDE4, in particular PDE4B, may be an efficient approach for treatment alcoholism and heroin dependence [This work was supported by research grants from NIH/NIAAA (AA020042; to HTZ), National Nature Science Foundation of China (30870894; to JHL/81071077; to WHZ), and National Basic Research Program of China (2009CB522008; to WHZ)].