title: Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula.
abstract: Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K+channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs. We report here that in rats at 24 h withdrawal from systemic ethanol administration (either by intraperitoneal injection, 2 g/kg, twice/day, for 7 days; or intermittent drinking 20% ethanol in a two-bottle free choice protocol for 8 weeks), the basal firing rate and the excitability of LHb neurons in brain slices was higher, whereas the amplitude of medium afterhyperpolarization and M-type K+currents were smaller, when compared to ethanol naive rats. Concordantly, M-channel blocker (XE991)-induced increase in the spontaneous firing rate in LHb neurons was smaller. The protein expression of M-channel subunits, KCNQ2/3 in the LHb was also smaller. Moreover, anxiety levels (tested in open field, marble burying, and elevated plus maze) were higher, which were alleviated by LHb inhibition either chemogenetically or by local infusion of the M-channel opener, retigabine. Intra-LHb infusion of retigabine also reduced ethanol consumption and preference. These findings reveal an important role of LHb M-channels in the expression of AUDs and ADs, and suggest that the M-channels could be a potential therapeutic target for alcoholics.
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Seungwoo
authors.identifier: http://orcid.org/0000-0003-1301-8480
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Wanhong
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Rao
authors.initials: R
authors.lastname: Fu
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gregor
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Kresimir
authors.initials: K
authors.lastname: Krnjevic
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bekker
authors.affiliation: Department of Anesthesiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.|Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Ye
mesh_terms: D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D019262:Habenula / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D046509:Tissue Culture Techniques
chemical_list: D002492:Central Nervous System Depressants; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000431:Ethanol