Differential change in neuroactive steroid sensitivity during ethanol withdrawal.
The progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P or allopregnanolone) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABA(A) receptors, recent findings suggest that sensitivity to 3alpha,5alpha-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 3alpha,5alpha-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 3alpha,5alpha-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3alpha,5alpha-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 3alpha,5alpha-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3alpha,5alpha-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3alpha,5alpha-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3alpha,5alpha-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3alpha,5alpha-P.
Finn
D A
DA
Portland 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
Gallaher
E J
EJ
Crabbe
J C
JC
D000280:Administration, Inhalation; D020270:Alcohol Withdrawal Seizures / Q000517:prevention & control; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001007:Anxiety / Q000209:etiology; D001259:Ataxia / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009126:Muscle Relaxation / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity*; D011280:Pregnanolone / Q000494:pharmacology*; D011863:Radioimmunoassay; D013045:Species Specificity; D013256:Steroids / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000209:etiology* / Q000378:metabolism*; D013997:Time Factors
D000927:Anticonvulsants; D013256:Steroids; D000431:Ethanol; D011280:Pregnanolone; D010433:Pentylenetetrazole