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

Abstract

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acid A (GABA A ) 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 hours prior to an injection of EtOH (4 g/kg i.p.) or saline. Handlinginduced convulsions (HICs) were scored at baseline, and then over a 24 hr 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 hrs). In a final study, retro-orbital blood samples were collected at 30, 60, 120, and 240 minutes 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. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 May 25. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe progesterone metabolite allopregnanolone (ALLO; 3α-hydroxy-5α-pregnan-20-one) is a potent positive modulator of γ-aminobutyric acid A (GABA A ) receptors that exerts anxiolytic, sedative, anticonvulsant, and locomotor stimulant effects in animals (Paul and Purdy, 1992;Lambert et al., 1995;Gasior et al., 1999;Rupprecht and Holsboer, 1999;Belelli and Lambert, ...

A New Look at the 5?-Reductase Inhibitor Finasteride

“…In contrast, finasteride increased acute withdrawal severity in female mice of both inbred strains. With this acute ethanol procedure, pretreatment with finasteride did not alter blood ethanol concentration, nor did it alter plasma corticosterone or 17â-estradiol levels in a manner that could explain the sex difference in finasteride's effect on acute ethanol withdrawal severity (59). Overall, finasteride pretreatment produced comparable effects in the acute and chronic ethanol withdrawal models in male mice, whereas it produced opposite effects in the female mice.…”

“…Since the terminal elimination half-life of finasteride in the circulation in humans is 4.7 to 7.1 h (132), we presumed that the use of an acute ethanol withdrawal procedure would allow the clearance of finasteride prior to ethanol injection, reducing or eliminating this potential interaction with ethanol metabolism. Using this model, results from our laboratory suggest that pretreatment with finasteride decreased acute withdrawal severity, measured by HICs, in male C57BL/6J and DBA/2J mice (59). In contrast, finasteride increased acute withdrawal severity in female mice of both inbred strains.…”

Chronic ethanol exposure leads to divergent control of dopaminergic synapses in distinct target regions

“…Both of these paradigms resulted in decreased body weight compared to control animals (data not shown) and increased corticosterone levels. It is unclear as to the event, ethanol exposure versus withdrawal, that precipitated the increase in corticosterone levels, as acute ethanol exposure causes an increase in corticosterone levels (Gorin-Meyer et al, 2007).…”

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

“…We have recently reported that the anticonvulsant effect of ALLO was decreased during ethanol withdrawal in male WSP mice, whereas sensitivity was unchanged in male WSR mice . Based on these data, the purpose of the present study was to examine sensitivity to the anticonvulsant effect of ALLO during ethanol withdrawal in female WSP and WSR mice, since female rodents display fewer physical symptoms of withdrawal (Devaud & Chadda, 2001;Gorin-Meyer et al, 2007;Veatch et al, 2007) and have higher circulating plasma ALLO levels than males (Finn et al, 2004b;Morrow et al, 1999;Paul and Purdy, 1992). Sensitivity to the anticonvulsant effect of ALLO during ethanol withdrawal was examined, and circulating hormone levels of progesterone, corticosterone, and estradiol were measured.…”