Inhibition of phosphodiesterase‐4 (PDE4) by roflumilast decreases ethanol consumption

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Excessive alcohol drinking normally causes alcoholism, which is one of the most damaging psychiatric disorders in the world. However, there are no ideal treatments for alcoholism in clinic. Phosphodiesterase‐4, an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), may play an important role in the regulation of ethanol consumption. This is supported by the findings that inhibition of PDE4 by rolipram, a prototypic PDE4 inhibitor, reduces ethanol intake and self‐administration. Roflumilast, another selective PDE4 inhibitor, has been approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of interest to know whether roflumilast altered ethanol consumption. The two‐bottle choice paradigm was used to assess ethanol intake and preference in C57BL/6J mice treated with roflumilast (1, 3, or 10 mg/kg) or rolipram (0.5 mg/kg; positive control). The effect of roflumilast was verified using ethanol drinking‐in‐dark. Locomotor activity was determined using the open‐field test. Roflumilast decreased ethanol intake and preference in two‐bottle choice in a dose‐dependent manner, with the significant change at the highest dose (10 mg/kg) of roflumilast, similar to rolipram. Neither roflumilast nor rolipram affected sucrose or quinine drinking, although roflumilast at the highest dose decreased locomotor activity. These data provide additional demonstration for the role of PDE4 in ethanol intake and suggest that roflumilast may be beneficial for treatment of alcoholism.