title: Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption.
abstract: Alcohol use disorders (AUDs) are a major public health issue and produce enormous societal and economic burdens. Current Food and Drug Administration (FDA)-approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. It is therefore essential to find improved medications for the management of AUDs. Emerging evidence suggests that anticonvulsants are a promising class of drugs for treating individuals with AUDs. In these studies, we used integrative functional genomics to demonstrate that genes that encode Kv7 channels (i.e. Kcnq2/3) are related to alcohol (ethanol) consumption, preference and acceptance in rodents. We then tested the ability of the FDA-approved anticonvulsant retigabine, a Kv7 channel opener, to reduce voluntary ethanol consumption of Wistar rats in a two-bottle choice intermittent alcohol access paradigm. Systemic administration and microinjections of retigabine into the nucleus accumbens significantly reduced alcohol drinking, and retigabine was more effective at reducing intake in high- versus low-drinking populations of Wistar rats. Prolonged voluntary drinking increased the sensitivity to the proconvulsant effects of pharmacological blockade of Kv7 channels and altered surface trafficking and SUMOylation patterns of Kv7.2 channels in the nucleus accumbens. These data implicate Kcnq2/3 in the regulation of ethanol drinking and demonstrate that long-term drinking produces neuroadaptations in Kv7 channels. In addition, these results have identified retigabine as a potential pharmacotherapy for treating AUDs and Kv7 channels as a novel therapeutic target for reducing heavy drinking.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: McGuier
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Griffin
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gass
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Padula
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. mulholl@musc.edu.|Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. mulholl@musc.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Mulholland
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology; D000428:Alcohol Drinking / Q000503:physiopathology*; D020270:Alcohol Withdrawal Seizures / Q000139:chemically induced; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D023281:Genomics; D051658:KCNQ2 Potassium Channel / Q000187:drug effects* / Q000235:genetics; D051659:KCNQ3 Potassium Channel / Q000187:drug effects* / Q000235:genetics; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects*; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017208:Rats, Wistar; D058207:Sumoylation / Q000187:drug effects; D055697:Taste Perception / Q000187:drug effects
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000427:Alcohol Deterrents; D000873:Anthracenes; D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; C101866:ezogabine
keywords: Alcohol; Kcnq; Kv7 channels; SUMOylation; nucleus accumbens; retigabine