ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2, is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed. Compulsive drinking putatively involves a transition to dorsal (vs. ventral) striatal control over drinking and a relative underactivity of indirect pathway MSNs (iMSNs) that enable adaptive behavioral selection in contrast to overactive direct pathway MSNs (dMSNs) that drive drinking behaviors. Compulsive drinking also involves a shift to dorsal (caudate-putamen) from ventromedial (nucleus accumbens) striatal control of ethanol-related behavior. Guided by novel preliminary data, this multidisciplinary project tests the overarching hypothesis that decreasing dorsal striatal phosphodiesterase 10A (PDE10A) type 2 activity in indirect medium spiny neurons (MSN) reduces compulsive drinking. In 4 Specific Aims, we seek to fill molecular, circuitry, pharmacological, behavioral and human genetic gaps in our understanding of the role of PDE10A isoforms in activation of distinct striatal MSN pathways and compulsive drinking. Aim 1 seeks to identify translatable PDE10A inhibitors that reduce compulsive-like ethanol self-administration, with consideration of enzyme off-rate, lipophilic efficiency and neuroactivational effects on distinct MSN circuits. Aim 2 will intersect Adora2a-Cre rats with expression of a floxed, validiated PDE10A shRNA to knockdown dorsal iMSN PDE10A in order to determine this the role of caudate-putamen PDE10A in iMSNs in escalated and aversion-resistant self- administration. Aim 3 seeks to determine the causal role of the striatal-restricted, membrane-associated PDE10A2 isoform in compulsive-like ethanol intake. Finally, Aim 4 seeks PDE10A gene variants that associate with problematic alcohol use as well as their functional, expression, and psychiatric genetic correlates. The collective work of our assembled, multidisciplinary collaborative team will shed light on the neurobiological and genetic role of PDE10A isoforms in distinct striatal circuits and compulsive drinking behaviors as well as the potential impact of novel translatable PDE10A inhibitors to treat AUD.