Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula.

Neuropharmacology

Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, 07103, USA. Electronic address:

Published: February 2020

Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HTRs). Also, 5-HTR activation is known to inhibit M-current in mouse hypothalamic neurons. The present study investigated whether LHb 5-HTRs and M-channels contribute to AB in adult male Long-Evans rats. We used the intermittent-access to 20% ethanol two-bottle free-choice drinking paradigm to induce dependence. We measured AB with the elevated plus-maze, open-field, and marble-burying tests at 24 h withdrawal. We found that intra-LHb infusion of SB242084, a selective 5-HTR antagonist alleviated AB and reduced the elevated c-Fos expression in the LHb of Post-EtOH rats. By contrast, intra-LHb infusion of the selective 5-HTR agonist WAY161503 induced AB and increased c-Fos expression in the LHb in alcohol-naive but not Post-EtOH rats. Also, intra-LHb SB242084 significantly reduced self-administration of alcohol intake in the operant chambers. Furthermore, both 5-HTR protein levels and 5-HIAA/5-HT ratio was increased in the LHb of Post-EtOH rats. Finally, intra-LHb SB242084 increased LHb KCNQ2/3 membrane protein expression in Post-EtOH rats. Collectively, these results suggest that enhanced LHb 5-HTR signaling that interacted with M-channels triggers AB in Post-EtOH rats and that 5-HTRs may be a promising target for treating comorbid anxiety disorders in alcoholics.

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http://dx.doi.org/10.1016/j.neuropharm.2019.107863DOI Listing

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