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Differential change in neuroactive steroid sensitivity during ethanol withdrawal
D A Finn1, E J Gallaher, J C Crabbe
1Portland Alcohol Research Center, Research Service, Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, OR 97201, USA. finnd@ohsu.edu
The Journal of Pharmacology and Experimental Therapeutics
|December 22, 1999
Summary
Ethanol withdrawal alters sensitivity to allopregnanolone, a progesterone metabolite. While anticonvulsant effects were enhanced in C57BL/6 mice, muscle relaxant effects decreased in both C57BL/6 and DBA/2 strains.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Chronic ethanol (EtOH) exposure leads to GABA(A) receptor tolerance.
- Allopregnanolone (3alpha,5alpha-P), a progesterone metabolite, modulates GABA(A) receptors.
- Sensitivity to allopregnanolone may change during EtOH withdrawal, differing between mouse strains.
Purpose of the Study:
- To investigate differential sensitivity to allopregnanolone's pharmacological effects during EtOH withdrawal in C57BL/6 (B6) and DBA/2 (D2) mice.
- To determine if genotype influences EtOH withdrawal-induced changes in allopregnanolone sensitivity.
Main Methods:
- Male B6 and D2 mice were exposed to EtOH vapor or air for 72 hours.
- During EtOH withdrawal, mice received varying doses of allopregnanolone (0-17 mg/kg).
- Behavioral tests assessed activity, anxiolysis (elevated plus maze), muscle relaxation, ataxia, and seizure protection (pentylenetetrazol).
Main Results:
- Allopregnanolone's anticonvulsant effect was enhanced during EtOH withdrawal in B6 mice, but not D2 mice.
- Sensitivity to allopregnanolone's muscle relaxant effects decreased in both EtOH-withdrawing B6 and D2 mice.
- A trend towards decreased anxiolytic sensitivity to allopregnanolone was observed in B6 mice during withdrawal.
Conclusions:
- Sensitization to allopregnanolone's anticonvulsant effects during EtOH withdrawal is genotype-dependent.
- This sensitization does not extend to all pharmacological effects, such as muscle relaxation.
- Withdrawal-induced changes in allopregnanolone sensitivity are complex and do not generalize across all effects or genotypes.