Neural serotonergic circuits for controlling long-term voluntary alcohol consumption in mice

Alcohol-use-disorders are chronic relapsing illnesses, often co-morbid with anxiety. We have previously shown using the “drinking-in-the-dark” model in mice that the stimulation of the serotonin receptor 1A (5-HT(1A)) reduces ethanol binge-drinking behaviour and withdrawal-induced anxiety. The 5-HT(1A) receptor is located either on Raphe neurons as autoreceptors, or on target neurons as heteroreceptors. By combining a pharmacological approach with biased agonists targeting the 5-HT(1A) auto- or heteroreceptor and a chemogenetic approach (DREADDs), here we identified that ethanol-binge drinking behaviour is dependent on 5-HT(1A) autoreceptors and 5-HT neuronal function, with a transition from DRN-dependent regulation of short-term (6 weeks) ethanol intake, to MRN-dependent regulation after longer ethanol exposure (12 weeks). We further identified a serotonergic microcircuit (5-HT(MRN→DG)) originating from the MRN and projecting to the dentate gyrus (DG) of the hippocampus, that is specifically affected by, and modulates long-term ethanol consumption. The present study indicates that targeting Raphe nuclei 5-HT(1A) autoreceptors with agonists might represent an innovative pharmacotherapeutic strategy to combat alcohol abuse.