Chronic ethanol exposure in mice evokes pre- and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons.

Abstract

Background and purpose: GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABA_A receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed.

Experimental approach: We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABA_B receptor (GABA_BR) in ethanol-naïve mice to investigate its impact on anxiety-related behaviour.

Key results: The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABA_BR inhibition, suggesting chronic ethanol strengthens the GABA_BR-dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired-pulse depression of GABA_A receptor-dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol-treated mice was reversed by GABA_BR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABA_BR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (K_ir3) channel activity. Mimicking this adaptation enhanced anxiety-related behaviour in ethanol-naïve mice.

Conclusions and implications: Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre- and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety-related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder.