Alcohol-Induced Tolerance and Physical Dependence in Mice With Ethanol Insensitive α1 GABAA Receptors
Article first published online: 20 NOV 2008
Copyright © 2008 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 33, Issue 2, pages 289–299, February 2009
How to Cite
Werner, D. F., Swihart, A. R., Ferguson, C., Lariviere, W. R., Harrison, N. L. and Homanics, G. E. (2009), Alcohol-Induced Tolerance and Physical Dependence in Mice With Ethanol Insensitive α1 GABAA Receptors. Alcoholism: Clinical and Experimental Research, 33: 289–299. doi: 10.1111/j.1530-0277.2008.00832.x
- Issue published online: 22 JAN 2009
- Article first published online: 20 NOV 2008
- Received for publication March 11, 2008; accepted September 17, 2008.
- γ-Aminobutyric Acid;
- γ-Aminobutyric Acid Type A Receptors;
- Gene Knockin Mice;
Background: Although many people consume alcohol (ethanol), it remains unknown why some become addicted. Elucidating the molecular mechanisms of tolerance and physical dependence (withdrawal) may provide insight into alcohol addiction. While the exact molecular mechanisms of ethanol action are unclear, γ-aminobutyric acid type A receptors (GABAA-Rs) have been extensively implicated in ethanol action. The α1 GABAA-R subunit is associated with tolerance and physical dependence, but its exact role remains unknown. In this report, we tested the hypothesis that α1-GABAA-Rs mediate in part these effects of ethanol.
Methods: Ethanol-induced behavioral responses related to tolerance and physical dependence were investigated in knockin (KI) mice that have ethanol-insensitive α1 GABAA-Rs and wildtype (WT) controls. Acute functional tolerance (AFT) was assessed using the stationary dowel and loss of righting reflex (LORR) assays. Chronic tolerance was assessed on the LORR, fixed speed rotarod, hypothermia, and radiant tail-flick assays following 10 consecutive days of ethanol exposure. Withdrawal-related hyperexcitability was assessed by handling-induced convulsions following 3 cycles of ethanol vapor exposure/withdrawal. Immunoblots were used to assess α1 protein levels.
Results: Compared with controls, KI mice displayed decreased AFT and chronic tolerance to ethanol-induced motor ataxia, and also displayed heightened ethanol-withdrawal hyperexcitability. No differences between WT and KI mice were seen in other ethanol-induced behavioral measures. Following chronic exposure to ethanol, control mice displayed reductions in α1 protein levels, but KIs did not.
Conclusions: We conclude that α1-GABAA-Rs play a role in tolerance to ethanol-induced motor ataxia and withdrawal-related hyperexcitability. However, other aspects of behavioral tolerance and physical dependence do not rely on α1-containing GABAA-Rs.