Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats

Abstract

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRF^CeA-BNST pathway is mediated by inhibition of the CRF-CRF₁ system and inhibition of BNST cell firing. These results suggest that the CRF^CeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.

Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.