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Neural Serotonergic Circuits for Controlling Long-term Voluntary Alcohol Consumption in Mice

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Journal Mol Psychiatry
Date 2022 Oct 4
PMID 36195637
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Abstract

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) reduces ethanol binge-drinking behaviour and withdrawal-induced anxiety. The 5-HT 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 auto- or heteroreceptor and a chemogenetic approach (DREADDs), here we identified that ethanol-binge drinking behaviour is dependent on 5-HT 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) 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 autoreceptors with agonists might represent an innovative pharmacotherapeutic strategy to combat alcohol abuse.

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