AbstractBackgroundA prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self‐administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ‐8 (TARP γ‐8). This study evaluated the preclinical efficacy of JNJ‐55511118, a novel, selective, high‐affinity inhibitor of TARP γ‐8‐bound AMPARs, in reducing chronic operant alcohol self‐administration.MethodsSeparate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR‐4 schedule of reinforcement. After a 40‐day baseline, JNJ‐55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self‐administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded.ResultsDuring baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ‐55511118 decreased multiple parameters of alcohol self‐administration but did not reduce behavior‐matched sucrose‐only self‐administration. JNJ‐55511118 had no effect on sweetened alcohol or sucrose self‐administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ‐55511118 (1 mg/kg) had no effect on open‐field activity in male mice.ConclusionsThis study shows for the first time that TARP γ‐8‐bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ‐55511118 in reducing alcohol self‐administration in male mice suggests that inhibition of TARP γ‐8‐bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.