Pharmacological and genetic evidence of a role for phosphodiesterase 10A in high ethanol intake

About 1 in 8 Americans suffer from alcohol use disorder (AUD), a chronic, disabling, deadly disorder characterized by an inability to control drinking despite adverse outcomes. Only 1 in 5 individuals receive treatment, and new therapeutic targets for AUD are of great interest. The present embargoed preprint reports that: 1) systemic administration of a potent, selective phosphodiesterase 10A (PDE10A) inhibitor dose-dependently (0.2, 0.4 mmol/kg) reduced fixed- and progressive-ratio operant ethanol self-administration in post-dependent rats during protracted abstinence from chronic intermittent ethanol (CIE) vapor exposure, 2) systemic administration of the PDE10A inhibitor reduced 2-bottle choice voluntary ethanol intake in post-dependent CIE floxed littermate controls, while not altering drinking in Pde10a2-deficient mice, 3) system administration of the inhibitor unexpectedly reduced Egr1 and Fos immediate-early gene expression (IEG) in the dorsal striatum, without altering IEG expression in Pde10a2-deficient mice, 4) the PDE10A inhibitor also acutely altered striatal expression of medium spiny neuron markers, including Drd1, Drd2, and Penk expression, 5) REGENIE analyses of human PDE10A gene variants in the UK Biobank and All of Us datasets identified a significant association of PDE10A with alcohol use-attributable ICD10 diagnoses and weekly intake, and 6) MAGMA analyses found that Gene Ontology (GO) gene sets for cAMP binding, cAMP PDE activity, and regulation of cAMP-dependent protein kinase A (PKA) associated with problematic alcohol drinking and EtOH poisoning. The cAMP PDE associations involved both PDE4B and PDE10A variants. The collective pharmacological and genetic evidence supports a role for phosphodiesterase 10A in heavy drinking.