OBJECTIVE Since cyclic AMP (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets.Phosphodiesterase 4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, plays a critical role in regulating its intracellular levels.Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.METHODS Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (V/V) ethanol and 10% (W/V) sucrose operant oral serf-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125,0.025, and 0.05 mg·kg-1 , s.c.) ; rolipram at higher doses (0.05,0.1, and 0.2 mg·kg-1 , s.c.) was tested to determine its impact on the intake of ethanol, sucrose, or water using the two-bottle choice drinking paradigm.Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.RESULTS Acute administration of rolipram dose-dependently reduced operant self-administration of 5% ethanol, but had no effect on 10% sucrose responding.Time-course assessment revealed a significant anti-drinking effect of rolipram (0.1 and 0.2 mg·kg-1) in continuous-and intermittent-access to ethanol at 5% or 10%, respectively.Moreover, chronic rolipram treatment time-dependently decreased 5% ethanol consumption and preference during treatment days and after the termination of rolipram administration.Rolipram at the highest doses (0.1 and 0.2 mg· kg-1) did decrease locomotor activity, but the effect lasted only 10 and 20 rain, respectively, which did not likely alter long-term ethanol drinking.CONCLUSION These results suggest that PDF4 plays a role in alcohol seeking and consumption behavior.Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.