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GABAA/α1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice

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Abstract

Rationale

The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved.

Objective

β-Carboline-3-carboxylate-t-butyl ester (β-CCt) and zolpidem act preferentially at GABAA receptors containing the α1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression.

Methods

Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists β-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period.

Results

Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or β-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg β-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation.

Conclusions

Benzodiazepine antagonists, particularly those acting preferentially at GABAA/α1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.

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Acknowledgements

We acknowledge support by USPHS research grants AA13983, DA02632, DA11792, and grants from the Alcoholic Beverage Medical Research Foundation. We are grateful to Mr. J. Thomas Sopko, Mr. Daaniel Heerewijn and Ms. Sara Faccidomo who provided outstanding support.

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Authors and Affiliations

  1. Department of Psychology, Tufts University, Bacon Hall, 530 Boston Avenue, Medford, MA 02155, USA

    Rosa M. M. de Almeida & Klaus A. Miczek

  2. Centro de Ciências da Saúde, Unisinos, São Leopoldo, RS, Brazil

    Rosa M. M. de Almeida

  3. Department of Psychiatry, Pharmacology and Neuroscience, Tufts University, Boston, Massachusetts, USA

    Klaus A. Miczek

  4. New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA

    James K. Rowlett

  5. Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA

    James M. Cook & Wenyuan Yin

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  1. Rosa M. M. de Almeida
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  2. James K. Rowlett
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  3. James M. Cook
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  4. Wenyuan Yin
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  5. Klaus A. Miczek
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Correspondence to Klaus A. Miczek.

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de Almeida, R.M.M., Rowlett, J.K., Cook, J.M. et al. GABAA/α1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice. Psychopharmacology 172, 255–263 (2004). https://doi.org/10.1007/s00213-003-1661-1

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  • DOI: https://doi.org/10.1007/s00213-003-1661-1

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