Selective inhibition of phosphodiesterase 7 enzymes reduces alcohol drinking and seeking in animal models of alcohol use disorders

Alcohol use disorder (AUD) is a major cause of disabilities and, despite a few medications having been developed, still represents a largely unmet medical need. We have recently developed a new series of brain-penetrant molecules that selectively inhibit phosphodiesterase-7 (PDE7) enzymes. The PDE7 isoform encompasses two members, PDE7A and PDE7B. Both are cAMP-specific enzymes highly expressed in brain regions known to play a role in the modulation of alcohol reinforcement and abuse.Here we tested the effect of OMSPDE79, a selective PDE7 inhibitor, on multiple well-validated models of AUD in the rat. First, we evaluated the effects of intraperitoneal (i.p.) administration of OMSPDE79 (0, 5, 7, 9 mg/kg) on alcohol self-administration and on cue and yohimbine-induced reinstatement of alcohol seeking in outbred Wistar rats. Next, we tested the effects of OMSPDE79 on the alcohol deprivation (ADE) model of relapse in Wistar rats with a long history of drinking. Finally, we assessed the effect of OMSPDE79 on home-cage drinking in Marchigian Sardinian alcohol-preferring (msP) rats, a genetic model of innate preference for alcohol that mimics some features of more advanced stages of AUD.We found that OMSPDE79 dose-dependently decreased alcohol self-administration as well as cue and yohimbine-induced reinstatement of alcohol seeking. OMSPDE79 also prevented ADE after protracted abstinence in Wistars and reduced alcohol drinking in msP rats. These effects were specific to alcohol as OMSPDE79 altered neither food nor water intake.Taken together, our findings strongly support the potential of OMSPDE79 as a novel therapeutic candidate in AUD.