TARP ɣ-8 is a target of ethanol that regulates self-administration and relapse in mice

Behavioral pathologies that characterize alcohol use disorder (AUD) are driven by the powerful reinforcing, or rewarding, properties of the drug. We have shown that glutamate AMPA receptor (AMPAR) activity is both necessary and sufficient for alcohol (ethanol) reinforcement. Transmembrane AMPAR regulatory protein (TARP) γ-8 is an essential auxiliary protein that regulates AMPAR expression and activity; however, the role of TARP ɣ-8 in AUD or other forms of addiction remains largely unexplored.

This study investigated the mechanistic role of TARP γ-8 in operant ethanol self-administration (model of primary reinforcement) and cue-induced reinstatement of ethanol-seeking behavior (model of conditioned reinforcement) using TARP ɣ-8 heterozygous null (+/-) mice. To determine if TARP ɣ-8 signaling is targeted by ethanol use, we evaluated protein expression of TARP γ-8, GluA1, CaMKII, and PSD-95 following ethanol self-administration.

A battery of tests evaluating food and water intake, taste reactivity, anxiety-like behavior, and object recognition memory showed no fundamental behavioral deficits in TARP γ-8 (+/-) mice, and no differences in response to acute ethanol or home-cage drinking as compared to wild-types. However, TARP γ-8 (+/-) mice exhibited significantly reduced acquisition and escalation of operant ethanol self-administration and reduced cue-induced reinstatement of ethanol-seeking behavior, with no differences in parallel sucrose-only controls. In wild-type mice, ethanol self-administration increased TARP γ-8 expression in the amygdala, nucleus accumbens, and hippocampus, and increased GluA1 expression in the amygdala and prefrontal cortex, compared to sucrose controls.

These findings highlight the specificity of TARP ɣ-8 regulation of ethanol reinforcement mechanisms and identify this crucial AMPAR auxiliary protein as a target of ethanol in reward-related brain regions, highlighting its potential for development of novel pharmacotherapies for AUD.