Genetic correlations with ethanol withdrawal severity

Crabbe, John C.; Young, Emmett R.; Kosobud, Ann

doi:10.1016/0091-3057(83)90233-2

Cited by 87 publications

(78 citation statements)

References 12 publications

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“…Acute EtOH withdrawal severity, measured by hourly HIC scores, AUC, and peak withdrawal severity, was significantly greater in DBA/2J versus C57BL/6J mice, consistent with previously observed strain differences (Crabbe et al, 1983;Crabbe, 1998;Roberts et al, 1992). Another interesting finding was that acute EtOH withdrawal severity (hourly HIC scores, AUC, and peak withdrawal severity) was significantly higher in male mice relative to female mice.…”

Section: Hic Datasupporting

confidence: 76%

“…These inbred strains are a well-documented genetic animal model of alcohol withdrawal severity, since DBA/2J mice exhibit more severe handling-induced convulsions (HICs, a sensitive measure of CNS sensitivity) than C57BL/J mice during both chronic (Crabbe et al, 1983;Crabbe, 1998) and (Finn et al, 2004c). However, the finding that finasteride significantly decreased BEC upon the initiation of withdrawal suggested that it might affect withdrawal severity via an alteration in EtOH pharmacokinetics (Finn et al, 2004c).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 54%

“…These inbred strains are a well-documented genetic animal model of alcohol withdrawal severity, since DBA/2J mice exhibit more severe handling-induced convulsions (HICs, a sensitive measure of CNS sensitivity) than C57BL/J mice during both chronic (Crabbe et al, 1983;Crabbe, 1998) and acute (Roberts et al, 1992) EtOH withdrawal. Although we hypothesized that decreasing endogenous ALLO levels would decrease GABAergic inhibition and increase chronic EtOH withdrawal severity, treatment with finasteride significantly reduced chronic EtOH withdrawal severity in DBA/2J versus C57BL/6J mice (Finn et al, 2004c).…”

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confidence: 99%

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

et al. 2007

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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, ...

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Section: Hic Datasupporting

confidence: 76%

Section: Nih-pa Author Manuscriptmentioning

confidence: 54%

“…These inbred strains are a well-documented genetic animal model of alcohol withdrawal severity, since DBA/2J mice exhibit more severe handling-induced convulsions (HICs, a sensitive measure of CNS sensitivity) than C57BL/J mice during both chronic (Crabbe et al, 1983;Crabbe, 1998) and acute (Roberts et al, 1992) EtOH withdrawal. Although we hypothesized that decreasing endogenous ALLO levels would decrease GABAergic inhibition and increase chronic EtOH withdrawal severity, treatment with finasteride significantly reduced chronic EtOH withdrawal severity in DBA/2J versus C57BL/6J mice (Finn et al, 2004c).…”

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confidence: 99%

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

et al. 2007

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“…In a chronic ethanol administration procedure, physical dependence was induced by exposure to 72 h of ethanol vapor, with mice receiving a total of 4 injections of a 50 mg/kg dose of finasteride (one 24 h prior to, and each day of the exposure to 72 h EtOH vapor or air; 35,60 The first study was conducted in the C57BL/6J and DBA/2J inbred strains that differ markedly in chronic alcohol withdrawal severity, as indexed by handling-induced convulsions (HICs), a sensitive measure of CNS excitability (DBA/2J @ C57BL/6J; 25,26). In general, treatment with finasteride produced a significant decrease in chronic ethanol withdrawal severity in DBA/2J vs. C57BL/6J mice (35).…”

Section: Effects Of Chronic Alcohol Exposure and Withdrawalmentioning

confidence: 99%

A New Look at the 5?-Reductase Inhibitor Finasteride

et al. 2006

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Finasteride is the first 5á-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5á-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5á-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3á-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of ã-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA A receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual-and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5á-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely re- 53

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“…Since this pioneering study, many subsequent studies with inbred strains of mice have shown a genetic influence on ethanol-induced withdrawal severity (Goldstein and Kakihana 1974;Griffiths and Littleton 1977;Grieve et al 1979;Crabbe et al 1983;Crabbe 1994, 1999). These strain comparisons have been useful in dissociating the role of individual differences in ethanol metabolism from those specific to ethanol's effects on the brain (e.g.…”

Section: Genetics Of Alcohol Dependence and Withdrawalmentioning

confidence: 97%