Inhibition of 5α-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice

Matthew Ford, Naomi Yoneyama, Moriah N. Strong, Andrea Fretwell, Michelle Tanchuck, Deborah (Deb) Finn

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background: Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABAA receptors, and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5α-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naïve mice. Methods: Male C57BL/6J (B6) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20% w/v β-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50), and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment, mice were permitted the inaugural 2-hour limited access to a 10% v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and subsequent FIN withdrawal (13 days) phases. Results: FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency, as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking, ALLO levels were decreased by 28% in the FIN-50 group. Conclusions: Although the exact mechanism is unclear, FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.

Original languageEnglish (US)
Pages (from-to)1408-1416
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume32
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Finasteride
Biosynthesis
Inbred C57BL Mouse
Drinking
Ethanol
Steroids
Pregnanolone
Neurotransmitter Agents
Water
Brain
Therapeutics
Injections
Cyclodextrins
GABA-A Receptors

Keywords

  • Alcohol
  • Allopregnanolone
  • Drinking Patterns
  • Finasteride
  • GABA Receptors
  • Neurosteroid Metabolism

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Medicine(all)

Cite this

Inhibition of 5α-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice. / Ford, Matthew; Yoneyama, Naomi; Strong, Moriah N.; Fretwell, Andrea; Tanchuck, Michelle; Finn, Deborah (Deb).

In: Alcoholism: Clinical and Experimental Research, Vol. 32, No. 8, 08.2008, p. 1408-1416.

Research output: Contribution to journalArticle

Ford, Matthew ; Yoneyama, Naomi ; Strong, Moriah N. ; Fretwell, Andrea ; Tanchuck, Michelle ; Finn, Deborah (Deb). / Inhibition of 5α-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice. In: Alcoholism: Clinical and Experimental Research. 2008 ; Vol. 32, No. 8. pp. 1408-1416.
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abstract = "Background: Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABAA receptors, and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5α-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-na{\"i}ve mice. Methods: Male C57BL/6J (B6) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20{\%} w/v β-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50), and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment, mice were permitted the inaugural 2-hour limited access to a 10{\%} v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and subsequent FIN withdrawal (13 days) phases. Results: FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency, as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking, ALLO levels were decreased by 28{\%} in the FIN-50 group. Conclusions: Although the exact mechanism is unclear, FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.",
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AU - Ford, Matthew

AU - Yoneyama, Naomi

AU - Strong, Moriah N.

AU - Fretwell, Andrea

AU - Tanchuck, Michelle

AU - Finn, Deborah (Deb)

PY - 2008/8

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N2 - Background: Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABAA receptors, and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5α-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naïve mice. Methods: Male C57BL/6J (B6) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20% w/v β-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50), and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment, mice were permitted the inaugural 2-hour limited access to a 10% v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and subsequent FIN withdrawal (13 days) phases. Results: FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency, as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking, ALLO levels were decreased by 28% in the FIN-50 group. Conclusions: Although the exact mechanism is unclear, FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.

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