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Benzodiazepines and heightened aggressive behavior in rats: reduction by GABAA/α1 receptor antagonists

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Abstract

Rationale

Positive modulators of the benzodiazepine/GABAA receptor complex can heighten aggressive behavior; the GABAA/α1 subunit may play a critical role in benzodiazepine-modulated aggressive behavior.

Objective

The carboline derivatives, β-CCt and 3-PBC, antagonists with preferential action at the GABAA receptors with α1 subunits, may antagonize benzodiazepine-heightened aggression, thus implicating the α1 subunit in heightened aggression.

Methods

The GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4c]-pyridin-3-ol (THIP) (0.01–3.0 mg/kg), and the benzodiazepine receptor agonists midazolam (0.3–3.0 mg/kg) and triazolam (0.003–3.0 mg/kg) were administered to adult male resident rats to assess the drugs’ effects on their aggressive behavior toward an intruder. Then β-CCt (0.3–10.0 mg/kg) and 3-PBC (0.3–17.0 mg/kg) were each administered in conjunction with midazolam. The salient elements of aggressive and non-aggressive behavior were measured by analyzing video recordings and encoding each behavioral act and posture in terms of its frequency and duration of occurrence.

Results

Midazolam significantly increased the duration of aggressive behaviors at 1.0 and 1.7 mg/kg, and triazolam increased attack bite frequency at 0.03 mg/kg, both implicating GABAA receptors with benzodiazepine binding sites in aggressive behavior. In the present dose range, THIP did not affect any behaviors. The broad-spectrum benzodiazepine antagonist, flumazenil (1.0 mg/kg), antagonized the aggression-heightening effects of midazolam. β-CCt (0.3–10.0 mg/kg) and 3-PBC (0.3–17.0 mg/kg) also antagonized the aggression-heightening effects of midazolam (1.0 mg/kg).

Conclusions

These results implicate both the GABAA γ and α1 subunits in benzodiazepine-heightened aggression.

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Acknowledgements

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

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Authors and Affiliations

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

    Shannon L. Gourley, Joseph F. DeBold & Klaus A. Miczek

  2. Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

    Wenyuan Yin & James Cook

  3. Departments of Psychiatry, Pharmacology, and Neuroscience, Tufts University, Medford, Mass., USA

    Klaus A. Miczek

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Correspondence to Klaus A. Miczek.

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Gourley, S.L., DeBold, J.F., Yin, W. et al. Benzodiazepines and heightened aggressive behavior in rats: reduction by GABAA/α1 receptor antagonists. Psychopharmacology 178, 232–240 (2005). https://doi.org/10.1007/s00213-004-1987-3

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