A neural substrate of compulsive alcohol use

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 PKC delta(+) inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for similar to 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 PKC delta in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.

Automated summary

Research using a footshock-punished alcohol self-administration procedure identified a subpopulation of rats showing punishment-resistant self-administration behavior, which was found to be a stable trait in a subset of rats and associated with activity in the CeA brain network. Activity of PKC delta(+) inhibitory neurons in the CeL accounted for a significant portion of variance in punishment-resistant alcohol taking, suggesting a potential therapeutic target for alcohol addiction.