Neurosteroid modulators of GABAA receptors differentially modulate ethanol intake patterns in male C57BL/6J mice

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Abstract

Background: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of γ-aminobutyric acid A (GABA A) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods: Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10E and water by lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. Results: The GABAA receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. Conclusions: The present findings suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.

Original languageEnglish (US)
Pages (from-to)1630-1640
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume29
Issue number9
DOIs
StatePublished - Sep 2005

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Pregnanolone
GABA-A Receptors
Inbred C57BL Mouse
Modulators
Neurotransmitter Agents
Ethanol
Drinking
Aminobutyrates
Saccharin
Self Administration
Cyclodextrins
gamma-Aminobutyric Acid

Keywords

  • Allopregnanolone
  • Bout Microarchitecture
  • Drinking Patterns
  • Epipregnanolone
  • Lickometer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

@article{540c7e0aa76c48a99c35b45d487f3c34,
title = "Neurosteroid modulators of GABAA receptors differentially modulate ethanol intake patterns in male C57BL/6J mice",
abstract = "Background: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of γ-aminobutyric acid A (GABA A) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods: Male C57BL/6J mice were initiated to consume an unsweetened 10{\%} v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10E and water by lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20{\%} w/v β-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. Results: The GABAA receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. Conclusions: The present findings suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.",
keywords = "Allopregnanolone, Bout Microarchitecture, Drinking Patterns, Epipregnanolone, Lickometer",
author = "Matthew Ford and Nickel, {Jeffrey D.} and Tamara Phillips and Finn, {Deborah (Deb)}",
year = "2005",
month = "9",
doi = "10.1097/01.alc.0000179413.82308.6b",
language = "English (US)",
volume = "29",
pages = "1630--1640",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - Neurosteroid modulators of GABAA receptors differentially modulate ethanol intake patterns in male C57BL/6J mice

AU - Ford, Matthew

AU - Nickel, Jeffrey D.

AU - Phillips, Tamara

AU - Finn, Deborah (Deb)

PY - 2005/9

Y1 - 2005/9

N2 - Background: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of γ-aminobutyric acid A (GABA A) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods: Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10E and water by lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. Results: The GABAA receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. Conclusions: The present findings suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.

AB - Background: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of γ-aminobutyric acid A (GABA A) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods: Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10E and water by lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. Results: The GABAA receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. Conclusions: The present findings suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.

KW - Allopregnanolone

KW - Bout Microarchitecture

KW - Drinking Patterns

KW - Epipregnanolone

KW - Lickometer

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U2 - 10.1097/01.alc.0000179413.82308.6b

DO - 10.1097/01.alc.0000179413.82308.6b

M3 - Article

VL - 29

SP - 1630

EP - 1640

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 9

ER -