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

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 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 receptor (GABAR) 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 GABAR inhibition, suggesting chronic ethanol strengthens the GABAR-dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired-pulse depression of GABA receptor-dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol-treated mice was reversed by GABAR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABAR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (K3) 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.