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Behavioral effects of flumazenil in the social conflict test in mice

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Abstract

Rationale

Flumazenil, a competitive antagonist of benzodiazepine receptors (BZRs), has been used as a probe to detect effects of putative endogenous ligands for BZRs in anxiety. Flumazenil is renowned for its highly inconsistent behavioral effects.

Objective

To ascertain effects of flumazenil in the social conflict test in mice, which provides complex measures for prediction of anxiolytic and anxiogenic activity of drugs in behaviorally different groups of animals.

Methods

Singly housed male mice treated with flumazenil (5, 20 or 80 mg/kg i.p.) or vehicle were paired with untreated non-aggressive group-housed male mice in a novel cage. Behavior was analyzed from video tapes of the social interactions in three populations of mice: timid (n=21), aggressive (n=11), and sociable (n=7). Levels of γ-aminobutyric acid (GABA) were measured in vivo in the prefrontal cortex.

Results

Flumazenil reduced timid (defensive-escape) and increased locomotor activities in timid mice. The drug reduced aggressive and increased sociable (social investigation) activities in aggressive mice. These behavioral changes were produced at the lowest dose of flumazenil tested (5 mg/kg) and were not increased further by higher doses of the drug (20 mg/kg or 80 mg/kg). A tendency to increased timidity was found after flumazenil in sociable mice. Concentrations of GABA were markedly higher in the prefrontal cortex of sociable mice than in timid or aggressive mice.

Conclusions

Flumazenil produced moderate anxiolytic-like behavioural changes and a slight anxiogenic-like effect. The present data might be reflecting antagonism of corresponding endogenous BZR ligands. However, these putative ligands seem to exert only modest modulatory influence.

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Acknowledgements

This work was supported by a research grant from Czech Ministry of Education VZ: J13/98:111200005 and from Grant Agency of Charles University in Prague GAUK 72/2001/C/3. Flumazenil was a gift from F. Hoffmann-La Roche Ltd, Basel, Switzerland. We also wish to thank Mrs. J. Vávrová from University Hospital in Hradec Králové for measurement of GABA concentrations.

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  1. Department of Pharmacology, Charles University, 3rd Faculty of Medicine, Ruská 87, 100 34, Prague 10, Czech Republic

    L. Uhlířová, M. Šustková-Fišerová & M. Kršiak

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  1. L. Uhlířová
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  2. M. Šustková-Fišerová
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  3. M. Kršiak
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Correspondence to M. Kršiak.

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Uhlířová, L., Šustková-Fišerová, M. & Kršiak, M. Behavioral effects of flumazenil in the social conflict test in mice. Psychopharmacology 171, 259–269 (2004). https://doi.org/10.1007/s00213-003-1583-y

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  • DOI: https://doi.org/10.1007/s00213-003-1583-y

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