A Single Alcohol Pre-exposure Alters Dorsolateral Striatal AMPA Receptor Dependent Binge and Compulsive-like Drinking

Abstract

Background Compulsive alcohol drinking is a defining characteristic of alcohol use disorder and the dorsolateral striatum (DLS) is implicated in regulating this inflexible behavior. AMPA receptors have been implicated in both goal-directed (dorsomedial striatal dependent) and DLS dependent inflexible behaviors with antagonism in the DLS and general DLS inhibition altering inflexible behavior including habit and compulsion. Discrepancies exist in the preclinical models used to investigate compulsive-like alcohol. The purpose of these experiments was to establish a robust model of compulsive-like quinine adulterated alcohol (QuA) drinking in C57BL/6J male and female mice, assess associated AMPA receptor protein expression in the dorsal striatum, and to antagonize DLS AMPA receptors during compulsive-like QuA drinking using a model of binge-like alcohol drinking, Drinking-in-the-Dark (DID). Methods In aim 1, C57BL/6J mice were allowed free access to 20% (v/v) alcohol (alcohol history), or water (water history) for two hours each day beginning three hours into the dark cycle for 23 days. On days 15 and 22 mice were given QuA to test for compulsive-like QuA drinking. 24-hours following the last DID session brain slices were taking for DLS and DMS AMPA receptor western blot. In aim 2, C57BL/6J mice were given a total of 21 days alcohol history, to establish a compulsive-like phenotype, or water history, prior to infusion. On days 22 and 24 mice were given a bilateral infusion of one of three concentrations of NBQX, an AMPA receptor antagonist, into the DLS, immediately prior to DID where the DID solution was either alcohol or QuA. Results We found that three weeks, not two, is sufficient to produce robust compulsive-like QuA drinking in C57BL/6J mice. We failed to replicate our compulsive-like DID model in aim 2 and found that infusion of NBQX reduced 2-hour alcohol drinking and reduced 2-hour QuA drinking when QuA was the second solution presented on infusion days in male water history mice only. We also found that NBQX reduced 20-minute front-loading in female alcohol history mice on alcohol intake and trended toward QuA intake. Overall locomotor activity was affected by drug infusions. Conclusions Together, these data suggest that compulsive-like alcohol drinking can be achieved following three-weeks DID and DLS infusion of NBQX reduces both alcohol and QuA drinking in a sex and drinking history dependent way, and these effects may be reliant on an initial single QuA or alcohol exposure.