Treatment with and withdrawal from finasteride alter ethanol intake patterns in male C57BL/6J mice: Potential role of endogenous neurosteroids?

Matthew Ford, Jeffrey D. Nickel, Deborah (Deb) Finn

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Exogenous administration of the γ-aminobutyric acid (GABA)-ergic neurosteroid allopregnanolone (ALLO) can increase ethanol intake in rats and mice. To determine the contribution of endogenous neurosteroids (i.e., ALLO and related pregnane steroids) in the regulation of established ethanol consumption patterns in male C57BL/6J (B6) mice, the 5α-reductase (5α-R) enzyme inhibitor, finasteride (FIN), was chronically administered and then subsequently withdrawn. Mice were provided daily 2-h limited access to a 10% vol/vol ethanol solution (10E) and water in lickometer chambers during the dark phase. Following the establishment of stable 10E intake patterns, mice were injected intraperitoneally with either vehicle (20% wt/vol 2-hydroxypropyl-β- cyclodextrin; n = 8) or FIN (50 mg/kg; n = 16) for 7 days. Effects of withdrawal from FIN treatment were subsequently assessed for an additional 7 days. Ethanol intakes were significantly decreased with acute FIN treatment (days 1-3) and during early withdrawal (days 1-3). Acute FIN treatment was also associated with an extended latency to first bout, reduced first bout size, and greatly attenuated sipper contact count during the initial 20-min interval of 10E access. These findings collectively indicated that acute FIN treatment markedly attenuated the initiation of 10E consumption during the limited access sessions. The influence of FIN on 10E intake patterns was largely dissipated with chronic treatment, suggesting that compensatory changes in neurosteroid modulation of inhibitory tone may have occurred. Thus, acute FIN treatment modulated ethanol intake patterns in a manner opposite to that previously demonstrated for a physiologically relevant, exogenous ALLO dose, consistent with the ability of a5α-R inhibitor to block ALLO biosynthesis. Manipulation of endogenous neurosteroid activity via biosynthetic enzyme inhibition or antagonism of steroid binding to the GABA type A receptor may prove to be a beneficial pharmacotherapeutic strategy in the intervention of alcohol abuse and alcoholism.

Original languageEnglish (US)
Pages (from-to)23-33
Number of pages11
JournalAlcohol
Volume37
Issue number1
DOIs
StatePublished - Aug 2006

Fingerprint

Finasteride
Inbred C57BL Mouse
withdrawal
Neurotransmitter Agents
Ethanol
Pregnanolone
antagonism
chamber
alcoholism
manipulation
abuse
alcohol
contact
regulation
water
ability
Alcoholism
Steroids
Aminobutyrates
Pregnanes

Keywords

  • Alcohol
  • Bout microarchitecture
  • Drinking patterns
  • Lickometer
  • Neurosteroid metabolism
  • Self-administration

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Behavioral Neuroscience
  • Neuroscience(all)
  • Toxicology
  • Health(social science)

Cite this

@article{38f86ef4eeb94670ae554247e7078210,
title = "Treatment with and withdrawal from finasteride alter ethanol intake patterns in male C57BL/6J mice: Potential role of endogenous neurosteroids?",
abstract = "Exogenous administration of the γ-aminobutyric acid (GABA)-ergic neurosteroid allopregnanolone (ALLO) can increase ethanol intake in rats and mice. To determine the contribution of endogenous neurosteroids (i.e., ALLO and related pregnane steroids) in the regulation of established ethanol consumption patterns in male C57BL/6J (B6) mice, the 5α-reductase (5α-R) enzyme inhibitor, finasteride (FIN), was chronically administered and then subsequently withdrawn. Mice were provided daily 2-h limited access to a 10{\%} vol/vol ethanol solution (10E) and water in lickometer chambers during the dark phase. Following the establishment of stable 10E intake patterns, mice were injected intraperitoneally with either vehicle (20{\%} wt/vol 2-hydroxypropyl-β- cyclodextrin; n = 8) or FIN (50 mg/kg; n = 16) for 7 days. Effects of withdrawal from FIN treatment were subsequently assessed for an additional 7 days. Ethanol intakes were significantly decreased with acute FIN treatment (days 1-3) and during early withdrawal (days 1-3). Acute FIN treatment was also associated with an extended latency to first bout, reduced first bout size, and greatly attenuated sipper contact count during the initial 20-min interval of 10E access. These findings collectively indicated that acute FIN treatment markedly attenuated the initiation of 10E consumption during the limited access sessions. The influence of FIN on 10E intake patterns was largely dissipated with chronic treatment, suggesting that compensatory changes in neurosteroid modulation of inhibitory tone may have occurred. Thus, acute FIN treatment modulated ethanol intake patterns in a manner opposite to that previously demonstrated for a physiologically relevant, exogenous ALLO dose, consistent with the ability of a5α-R inhibitor to block ALLO biosynthesis. Manipulation of endogenous neurosteroid activity via biosynthetic enzyme inhibition or antagonism of steroid binding to the GABA type A receptor may prove to be a beneficial pharmacotherapeutic strategy in the intervention of alcohol abuse and alcoholism.",
keywords = "Alcohol, Bout microarchitecture, Drinking patterns, Lickometer, Neurosteroid metabolism, Self-administration",
author = "Matthew Ford and Nickel, {Jeffrey D.} and Finn, {Deborah (Deb)}",
year = "2006",
month = "8",
doi = "10.1016/j.alcohol.2005.11.002",
language = "English (US)",
volume = "37",
pages = "23--33",
journal = "Alcohol",
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TY - JOUR

T1 - Treatment with and withdrawal from finasteride alter ethanol intake patterns in male C57BL/6J mice

T2 - Potential role of endogenous neurosteroids?

AU - Ford, Matthew

AU - Nickel, Jeffrey D.

AU - Finn, Deborah (Deb)

PY - 2006/8

Y1 - 2006/8

N2 - Exogenous administration of the γ-aminobutyric acid (GABA)-ergic neurosteroid allopregnanolone (ALLO) can increase ethanol intake in rats and mice. To determine the contribution of endogenous neurosteroids (i.e., ALLO and related pregnane steroids) in the regulation of established ethanol consumption patterns in male C57BL/6J (B6) mice, the 5α-reductase (5α-R) enzyme inhibitor, finasteride (FIN), was chronically administered and then subsequently withdrawn. Mice were provided daily 2-h limited access to a 10% vol/vol ethanol solution (10E) and water in lickometer chambers during the dark phase. Following the establishment of stable 10E intake patterns, mice were injected intraperitoneally with either vehicle (20% wt/vol 2-hydroxypropyl-β- cyclodextrin; n = 8) or FIN (50 mg/kg; n = 16) for 7 days. Effects of withdrawal from FIN treatment were subsequently assessed for an additional 7 days. Ethanol intakes were significantly decreased with acute FIN treatment (days 1-3) and during early withdrawal (days 1-3). Acute FIN treatment was also associated with an extended latency to first bout, reduced first bout size, and greatly attenuated sipper contact count during the initial 20-min interval of 10E access. These findings collectively indicated that acute FIN treatment markedly attenuated the initiation of 10E consumption during the limited access sessions. The influence of FIN on 10E intake patterns was largely dissipated with chronic treatment, suggesting that compensatory changes in neurosteroid modulation of inhibitory tone may have occurred. Thus, acute FIN treatment modulated ethanol intake patterns in a manner opposite to that previously demonstrated for a physiologically relevant, exogenous ALLO dose, consistent with the ability of a5α-R inhibitor to block ALLO biosynthesis. Manipulation of endogenous neurosteroid activity via biosynthetic enzyme inhibition or antagonism of steroid binding to the GABA type A receptor may prove to be a beneficial pharmacotherapeutic strategy in the intervention of alcohol abuse and alcoholism.

AB - Exogenous administration of the γ-aminobutyric acid (GABA)-ergic neurosteroid allopregnanolone (ALLO) can increase ethanol intake in rats and mice. To determine the contribution of endogenous neurosteroids (i.e., ALLO and related pregnane steroids) in the regulation of established ethanol consumption patterns in male C57BL/6J (B6) mice, the 5α-reductase (5α-R) enzyme inhibitor, finasteride (FIN), was chronically administered and then subsequently withdrawn. Mice were provided daily 2-h limited access to a 10% vol/vol ethanol solution (10E) and water in lickometer chambers during the dark phase. Following the establishment of stable 10E intake patterns, mice were injected intraperitoneally with either vehicle (20% wt/vol 2-hydroxypropyl-β- cyclodextrin; n = 8) or FIN (50 mg/kg; n = 16) for 7 days. Effects of withdrawal from FIN treatment were subsequently assessed for an additional 7 days. Ethanol intakes were significantly decreased with acute FIN treatment (days 1-3) and during early withdrawal (days 1-3). Acute FIN treatment was also associated with an extended latency to first bout, reduced first bout size, and greatly attenuated sipper contact count during the initial 20-min interval of 10E access. These findings collectively indicated that acute FIN treatment markedly attenuated the initiation of 10E consumption during the limited access sessions. The influence of FIN on 10E intake patterns was largely dissipated with chronic treatment, suggesting that compensatory changes in neurosteroid modulation of inhibitory tone may have occurred. Thus, acute FIN treatment modulated ethanol intake patterns in a manner opposite to that previously demonstrated for a physiologically relevant, exogenous ALLO dose, consistent with the ability of a5α-R inhibitor to block ALLO biosynthesis. Manipulation of endogenous neurosteroid activity via biosynthetic enzyme inhibition or antagonism of steroid binding to the GABA type A receptor may prove to be a beneficial pharmacotherapeutic strategy in the intervention of alcohol abuse and alcoholism.

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KW - Bout microarchitecture

KW - Drinking patterns

KW - Lickometer

KW - Neurosteroid metabolism

KW - Self-administration

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