Ethanol-induced suppression of GIRK-dependent signaling in the basal amygdala

Abstract

<b>Abstract ID 25419</b> <b>Poster Board 343</b> Ethanol exposure fosters neuroadaptations that regulate mood, learning, and goal-directed behavior. The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder (AUD). The GABAB receptor (GABABR) is a promising therapeutic target for AUD, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The impact of ethanol on GABABR-dependent signaling in the BLA was examined using slice electrophysiology following repeated ethanol injection and/or chronic intermittent exposure to ethanol vapor in mice. The relevance of ethanol-induced plasticity in the BLA was explored using tests of mood-related behavior and associative learning, combined with neuron-specific, viral genetic manipulations. The inhibitory effect of GABABR activation on principal neurons in the basal (BA) but not lateral (LA) sub-region of the mouse BLA was diminished following repeated ethanol exposure (t58=5.072, ****P&lt;0.001; N=30/group; unpaired Student9s t-test). This adaptation was attributable to the suppression of the G protein-gated inwardly rectifying K+ (GIRK) channel activity. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 was necessary for the ethanol-induced plasticity as the adaptation was not present in GIRK3KO mice exposed to ethanol (t42=0.3170, P=0.7528, N=22/group; unpaired Student9s t test). In wild type mice, exposure to ethanol altered several mood-related behaviors. In the light-dark box test ethanol-exposed animals spent less time on the light side (t22=3.208, **P=0.0041, N=12/group; unpaired Student9s t-test). In the marble burying test ethanol-exposed animals buried more marbles (t22=3.174, **P=0.0044, N=12/group; unpaired Student9s t-test). In the bottle-brush test ethanol-exposed animals had an increased irritability (t22=12.19, ****P=&lt;0.0001, N=12/group; unpaired Student9s t test). Importantly, all these behavioral effects were absent in ethanol exposed GIRK3KO mice: light-dark box (t16=1.719, P=0.1048, N=8-10/group; unpaired Student9s t test); marble burying (t16=0.2327, P=0.8189, N=8-10/group; unpaired Student9s t test); bottle-brush (t16=0.8220, P=0.4232, N=8-10/group; unpaired Student9s t test). Finally, some, but not all, of these ethanol exposure-dependent behavioral effects could be mimicked in ethanol naive mice by the selective suppression of GIRK channels in BA principal neurons. Therapeutic approaches designed to prevent this plasticity and/or enhance GIRK channel activity may prove useful for treatment of AUD. Grant Support KW: NIDA-DA034696, NIAA-AA027544; MET: NIAAA-AA025978; TRR: NIDA-DA007234; TRR &amp; BNV: UMN Doctoral Dissertation Fellowships; Viral Vector and Cloning Core/Viral Innovation Core: NIDA-DA048742-01A1; KW: Wallin Neuroscience Discovery Fund award.