Interaction of chronic ethanol exposure and finasteride: sex and strain differences.
The neurosteroid allopregnanolone (ALLOP) is a very potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride blocks the formation of ALLOP from progesterone and was recently found to reduce some effects of EtOH. Thus, the present studies were conducted to determine the effect of finasteride on chronic EtOH withdrawal severity in male and female C57BL/6 (B6) and DBA/2 (D2) mice. The animals were exposed to 72 h EtOH vapor or air and received four injections of finasteride (50 mg/kg ip) 24 h prior to, and each day of, the EtOH vapor exposure. Upon removal from the inhalation chambers, handling-induced convulsions (HICs) were measured hourly for the first 12 h and then again at 24 h. EtOH withdrawal severity was significantly greater in D2 than in B6 mice. Pretreatment with finasteride significantly decreased EtOH withdrawal severity only in the female D2 mice, produced a nonselective suppressive effect on HIC in male B6 and D2 mice, and did not significantly alter HIC in female B6 mice. Finasteride pretreatment significantly decreased blood EtOH concentration (BEC) upon initiation of withdrawal, suggesting that finasteride may affect withdrawal severity via an alteration in EtOH pharmacokinetics.
Finn
Deborah A
DA
Portland Alcohol Research Center, Department of Veterans Affairs Medical Center, VAMC Research (R&D-49), 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA. finnd@ohsu.edu
Long
Season L
SL
Tanchuck
Michelle A
MA
Crabbe
John C
JC
D000818:Animals; D019540:Area Under Curve; D000431:Ethanol / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D018120:Finasteride / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000032:analysis; D012727:Sex Characteristics; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D000431:Ethanol; D018120:Finasteride; D011280:Pregnanolone