GSBS Student Publications

Title

Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol

Student Author(s)

Linzy Hendrickson

GSBS Program

Neuroscience

UMMS Affiliation

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute

Date

11-5-2008

Document Type

Article

Medical Subject Headings

Animals; Cell Line; Corpus Striatum; Drug Tolerance; Electrophysiology; Ethanol; Feeding Behavior; Humans; Large-Conductance Calcium-Activated Potassium Channel beta; Subunits; Locomotion; Mice; Mice, Knockout

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology

Abstract

Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to alcohol exhibited by a naive subject can predict the likelihood of alcohol abuse. Thus, the determinants of acute tolerance are important to understand. Calcium- and voltage-gated (BK) potassium channels, consisting of pore forming alpha and modulatory beta subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK beta4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of beta4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the beta4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the beta4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from beta4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. In addition, beta4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, beta4 KO mice drink more than their WT counterparts. Taken together, these data indicate that the beta4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17543-8. Epub 2008 Nov 3. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

18981408