Ethanol-Induced Suppression of G Protein–Gated Inwardly Rectifying K+–Dependent Signaling in the Basal Amygdala

Ezequiel Marron Fernandez de Velasco, Megan E. Tipps, Bushra Haider, Anna Souders, Carolina Aguado, Timothy R. Rose, Baovi N. Vo, Margot C. DeBaker, Rafael Luján, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABABR (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The effect of ethanol on GABABR-dependent signaling in the BLA is unknown. Methods: GABABR-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the basal amygdala subregion (BA) to mood-related behavior. Results: The somatodendritic inhibitory effect of GABABR activation on principal neurons in the basal but not the lateral subregion of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of GIRK (G protein–gated inwardly rectifying K+) channel activity and was mirrored by a redistribution of GABABR and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal. Conclusions: The ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for the treatment of alcohol use disorder.

Original languageEnglish (US)
Pages (from-to)863-874
Number of pages12
JournalBiological psychiatry
Volume94
Issue number11
DOIs
StatePublished - Dec 1 2023

Bibliographical note

Publisher Copyright:
© 2023 Society of Biological Psychiatry

Keywords

  • Alcohol
  • Behavior
  • GABA receptor
  • Kir3
  • Neuroadaptation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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