Attenuation of the stimulant response to ethanol is associated with enhanced ataxia for a GABAA, but not a GABAB, receptor agonist

Sarah E. Holstein, Lauren Dobbs, Tamara Phillips

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: The γ-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABA B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.

Original languageEnglish (US)
Pages (from-to)108-120
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume33
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Ataxia
Ethanol
Muscimol
Baclofen
gamma-Aminobutyric Acid
GABA Uptake Inhibitors
GABA-B Receptor Agonists
Alcohols
Pharmacology
GABA-A Receptor Agonists
Aminobutyrates
Drug therapy
GABA Receptors
GABA-A Receptors
Hypnotics and Sedatives
Chemical activation
Drug Therapy

Keywords

  • Alcohol
  • Animal model
  • Drug abuse
  • Motor control
  • Stimulation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Attenuation of the stimulant response to ethanol is associated with enhanced ataxia for a GABAA, but not a GABAB, receptor agonist. / Holstein, Sarah E.; Dobbs, Lauren; Phillips, Tamara.

In: Alcoholism: Clinical and Experimental Research, Vol. 33, No. 1, 01.2009, p. 108-120.

Research output: Contribution to journalArticle

@article{bf2d10487faf4aca8bd7019a36db61ac,
title = "Attenuation of the stimulant response to ethanol is associated with enhanced ataxia for a GABAA, but not a GABAB, receptor agonist",
abstract = "Background: The γ-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABA B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.",
keywords = "Alcohol, Animal model, Drug abuse, Motor control, Stimulation",
author = "Holstein, {Sarah E.} and Lauren Dobbs and Tamara Phillips",
year = "2009",
month = "1",
doi = "10.1111/j.1530-0277.2008.00817.x",
language = "English (US)",
volume = "33",
pages = "108--120",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Attenuation of the stimulant response to ethanol is associated with enhanced ataxia for a GABAA, but not a GABAB, receptor agonist

AU - Holstein, Sarah E.

AU - Dobbs, Lauren

AU - Phillips, Tamara

PY - 2009/1

Y1 - 2009/1

N2 - Background: The γ-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABA B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.

AB - Background: The γ-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABA B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.

KW - Alcohol

KW - Animal model

KW - Drug abuse

KW - Motor control

KW - Stimulation

UR - http://www.scopus.com/inward/record.url?scp=58149202522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149202522&partnerID=8YFLogxK

U2 - 10.1111/j.1530-0277.2008.00817.x

DO - 10.1111/j.1530-0277.2008.00817.x

M3 - Article

C2 - 18945218

AN - SCOPUS:58149202522

VL - 33

SP - 108

EP - 120

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 1

ER -