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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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
Number of pages12
JournalScience Advances
Issue number34
Publication statusPublished - 18 Aug 2021


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