Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice

R. E. Gorin-Meyer, Kristine Wiren, M. A. Tanchuck, S. L. Long, N. Yoneyama, Deborah (Deb) Finn

Research output: Contribution to journalArticle

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Abstract

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors that can modulate ethanol (EtOH) withdrawal. The 5α-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 5α-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.

Original languageEnglish (US)
Pages (from-to)1302-1315
Number of pages14
JournalNeuroscience
Volume146
Issue number3
DOIs
StatePublished - May 25 2007

Fingerprint

Finasteride
Inbred DBA Mouse
Sex Characteristics
Ethanol
Pregnanolone
Neurotransmitter Agents
Corticosterone
Estradiol
Injections
GABA-A Receptors
Alcoholics
Oxidoreductases
Seizures
Pharmacokinetics
Steroids

Keywords

  • 5α-reductase
  • alcohol
  • allopregnanolone
  • convulsions
  • radioimmunoassay
  • steroid hormones

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice. / Gorin-Meyer, R. E.; Wiren, Kristine; Tanchuck, M. A.; Long, S. L.; Yoneyama, N.; Finn, Deborah (Deb).

In: Neuroscience, Vol. 146, No. 3, 25.05.2007, p. 1302-1315.

Research output: Contribution to journalArticle

Gorin-Meyer, R. E. ; Wiren, Kristine ; Tanchuck, M. A. ; Long, S. L. ; Yoneyama, N. ; Finn, Deborah (Deb). / Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice. In: Neuroscience. 2007 ; Vol. 146, No. 3. pp. 1302-1315.
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