Abstract
The progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α-P or allopregnanolone) is a potent positive modulator of γ-aminobutyric acidA (GABAA) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABAA receptors, recent findings suggest that sensitivity to 3α,5α-P is enhanced during EtOH withdrawal. In addition, EtOH-naive inbred strains of mice, which differ in EtOH withdrawal severity (DBA/2 ≫ C57BL/6), had marked differences in behavioral sensitivity to 3α,5α-P. Therefore, the present study was conducted to determine whether C57BL/6 (B6) and DBA/2 (D2) mice would be differentially sensitive to several of the pharmacological effects of 3α,5α-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3α,5α-P (0, 3.2, 10, or 17 mg/kg i.p.) and tested for activity and anxiolysis on the elevated plus maze, muscle relaxation, ataxia, and seizure protection following pentylenetetrazol. Sensitivity to the anticonvulsant effect of 3α,5α-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3α,5α-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3α,5α-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3α,5α-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3α,5α-P.
Footnotes
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Send reprint requests to: Deborah A. Finn, Ph.D., VAMC Research (R & D 12), 3710 SW U.S. Veterans Hospital Rd., Portland, OR 97201. E-mail: finnd{at}ohsu.edu
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↵1 This research was supported by U.S. Public Health Service Grant AA10760 from the National Institute on Alcohol Abuse and Alcoholism (to D.A.F. and J.C.C.) and a Merit Review Grant from the Department of Veterans Affairs (to J.C.C.).
- Abbreviations:
- EtOH
- ethanol
- GABA
- γ-aminobutyric acid
- 3α,5α-P
- 3α-hydroxy-5α-pregnan-20-one
- B6
- C57BL/6
- D2
- DBA/2
- WSP
- Withdrawal Seizure-Prone
- WSR
- Withdrawal Seizure-Resistant
- BEC
- blood EtOH concentration
- PTZ
- pentylenetetrazol
- MC twitch
- myoclonic twitch
- FF clonus
- face and forelimb clonus
- RB clonus
- running bouncing clonus
- THE
- tonic hindlimb extension
- RIA
- radioimmunoassay
- CORT
- corticosterone
- Received June 8, 1999.
- Accepted September 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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