Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice.
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride can block the formation of ALLO and other GABAergic neurosteroids and also reduce certain effects of EtOH. Treatment with finasteride during chronic EtOH exposure decreased EtOH withdrawal severity and blood EtOH concentrations (BECs), suggesting an additional effect of finasteride on EtOH pharmacokinetics. Thus, the purpose of the present study was to determine the effect of finasteride on acute EtOH withdrawal severity, to minimize the effect of finasteride on EtOH metabolism. Male and female C57BL/6J and DBA/2J mice received a pretreatment of finasteride (50 mg/kg i.p.) or vehicle 24 h prior to an injection of EtOH (4 g/kg i.p.) or saline. Handling-induced convulsions (HICs) were scored at baseline, and then over a 24 h period after EtOH or saline injection. In another experiment, plasma estradiol and corticosterone levels were assessed at selected time points (0, 2, 8, and 24 h). In a final study, retro-orbital blood samples were collected at 30, 60, 120, and 240 min post-EtOH administration to access finasteride's effects on EtOH clearance parameters. Pretreatment with finasteride increased acute EtOH withdrawal severity in female C57BL/6J and DBA/2J mice but decreased withdrawal severity in male mice of both strains. Finasteride did not alter BECs, EtOH clearance, estradiol, or corticosterone concentrations in a manner that appeared to contribute to the sex difference in finasteride's effect on acute EtOH withdrawal severity. These findings suggest that male and female C57BL/6J and DBA/2J mice differ in their sensitivity to changes in ALLO or other GABAergic neurosteroid levels during acute EtOH withdrawal. Sex differences in the modulation of GABAergic 5alpha-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.
Gorin-Meyer
R E
RE
Department of Behavioral Neuroscience (L-470), Oregon Health and Science University School of Medicine, and Portland Alcohol Research Center, Department of Veterans Affairs Medical Research, Portland, OR 97239-3098, USA.
Wiren
K M
KM
Tanchuck
M A
MA
Long
S L
SL
Yoneyama
N
N
Finn
D A
DA
D000208:Acute Disease; D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000097:blood; D003345:Corticosterone / Q000097:blood; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D005260:Female; D018120:Finasteride / Q000494:pharmacology*; D006234:Handling, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011863:Radioimmunoassay; D012640:Seizures / Q000139:chemically induced; D012727:Sex Characteristics; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology*
D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D000431:Ethanol; D004958:Estradiol; D018120:Finasteride; D013250:Steroid Hydroxylases; D003345:Corticosterone