Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ‐8 with JNJ‐55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self‐administration

Abstract

Background: A 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 selfadministration 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.Methods: Separate 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.Results: During 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. Conclusions:This 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.

Inhibition of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner

“…Moreover, lack of significant reductions in operant behavior during the initial onset of responding, or on reinforcer consumption (headpokes), suggests lack of memory deficits. This is consistent with our prior observation that systemic administration of JNJ-5 reduced alcohol self-administration by male, but not female, mice in the absence of motor effects (Hoffman et al 2021). Thus, blocking only the subclass of AMPARs associated with TARP γ-8 may provide therapeutic efficacy in the absence of negative side-effects; however, further work needs to explore the possibility of sexually dimorphic sensitivity to JNJ-5 (Hoffman et al 2021) and the potential nonspecific impact of higher doses in females.…”

“…This study is the first to examine TARP γ-8 as a driving force of the reinforcing effects of any drug of abuse via activity within a brain reward pathway and provides further support for the premise that targeting this AMPAR subclass may be a viable strategy for developing medications to treat behavioral pathologies associated with AUD (Hoffman et al 2021) or other neurological conditions (Maher et al 2017).…”

“…Our prior research shows that inhibition of TARP γ-8 bound AMPARs via systemic administration of the selective inhibitor JNJ-5 significantly decreases operant alcohol self-administration in C57BL/6J mice (Hoffman et al 2021). The present study extends this finding and identifies TARP γ-8 in the BLA as a novel site-specific molecular mechanism of the positive reinforcing effects of alcohol.…”

“…We have shown that alcohol self-administration increases pGluA1-S831 expression and synaptic insertion of calcium-permeable GluA2-lacking AMPARs (CP-AMPARs) in the BLA, and that membrane insertion of GluA1-containing AMPARs is required for the positive reinforcing effects of alcohol (Faccidomo et al 2021). Moreover, we recently found that systemic pharmacological inhibition of TARP γ-8 bound AMPARs significantly reduced operant alcohol self-administration by male, but not female, C57BL/6J mice (Hoffman et al 2021), which was the first evidence that TARP γ-8 mediates any form of substance abuse. Together, these findings suggest the novel hypothesis that TARP γ-8 regulates the positive reinforcing properties of alcohol via modulation of AMPAR activity in specific reward-related brain regions.…”

Shortening time for access to alcohol drives up front-loading behavior, bringing consumption in male rats to the level of females

“…One of the levers was active, in which a response (active lever press) consequently delivered 0.1 ml of fluid from a 15 rpm Razel syringe pump (Stamford, CT) to the appropriate well over 0.5 s. The fluid delivered was tap water in the 12-h training session and either water (control) or 10% (w/v) alcohol (ethanol) diluted in tap water (alcohol group) in subsequent training and testing sessions. The alternate lever was inactive, only recording the operant response (inactive lever press) without delivery of fluid, used as a measure of “non-discriminative lever pressing” [ 66 ]. The active lever was programmed to a fixed ratio 1 (FR1) schedule for training and its location was counterbalanced between each rat (half of the rats had an active left lever, and the other half had an active right lever).…”