The phosphodiesterase-4 inhibitor roflumilast decreases ethanol consumption in C57BL/6J mice

Abstract

Rationale: Alcohol use disorders have become one of the most damaging psychiatric disorders in the world; however, there are no ideal treatments in clinic. Phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), has been involved in alcohol use disorders. Roflumilast is the first PDE4 inhibitor approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of particular interest to researchers to determine whether roflumilast altered ethanol consumption.

Objectives: The present study tried to determine the effects of roflumilast on ethanol intake and preference.

Methods: We used the two-bottle choice paradigm 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 the ethanol drinking-in-dark (DID) test. Locomotor activity was examined using the open-field test. Intake of sucrose or quinine was also tested to determine whether natural reward preference and aversive stimuli were involved in the effect of PDE4 inhibitors.

Results: Similar to rolipram, roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in a dose-dependent manner, with significant changes at the dose of 10 mg/kg; in contrast, roflumilast did not affect sucrose or quinine drinking, although it decreased locomotor activity at the high dose within 3 h of treatment.

Conclusions: These data provide novel demonstration for the effect of roflumilast on ethanol consumption and suggest that roflumilast may be beneficial for treatment of alcoholism.

Keywords: C57BL/6J mice; Ethanol consumption; Phosphodiesterase-4 (PDE4); Roflumilast; cAMP signaling.