A neural substrate of compulsive alcohol use

Esi Domi*, Li Xu, Sanne Toivainen, Anton Nordeman, Francesco Gobbo, Marco Venniro, Yavin Shaham, Robert O. Messing, Esther Visser, Michel C. van den Oever, Lovisa Holm, Estelle Barbier, Eric Augier, Markus Heilig

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Alcohol intake remains controlled in a majority of users but becomes "compulsive,"i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKCδ+ inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for ∼75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKCδ in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.

Original languageEnglish
Article numbereabg9045
JournalScience advances
Volume7
Issue number34
DOIs
Publication statusPublished - Aug 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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