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 gamma-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.

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

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Psychopharmacology (Berl). 1990;101(4):525-32 PubMed

Psychopharmacology (Berl). 1990;101(3):396-402 PubMed

Peptides. 1998;19(5):841-8 PubMed

Brain Res. 1984 Sep 17;310(1):154-6 PubMed

Neurochem Res. 2002 Dec;27(12):1605-12 PubMed

Pharmacol Rev. 1998 Jun;50(2):291-313 PubMed

Neuropharmacology. 1991 Dec;30(12A):1263-7 PubMed

Br J Pharmacol. 1979 Mar;65(3):525-33 PubMed

Brain Res Mol Brain Res. 2002 Jul 15;104(1):103-9 PubMed

Prog Clin Biol Res. 1984;167:93-114 PubMed

Physiol Behav. 2000 Dec;71(5):509-16 PubMed

Br J Pharmacol. 1992 Jan;105(1):164-70 PubMed

Pharmacol Biochem Behav. 1986 Mar;24(3):525-9 PubMed

Psychopharmacology (Berl). 1993;111(4):415-22 PubMed

Psychopharmacology (Berl). 1993;110(4):451-9 PubMed

Psychopharmacology (Berl). 1983;80(2):192-5 PubMed

J Neurosci. 1988 Jan;8(1):289-95 PubMed

Physiol Behav. 1984 Sep;33(3):401-9 PubMed

Psychopharmacology (Berl). 2001 Sep;157(2):123-30 PubMed

Peptides. 1992 Nov-Dec;13(6):1219-25 PubMed

Psychopharmacology (Berl). 1992;108(1-2):205-9 PubMed

Neurosci Biobehav Rev. 2001 May;25(3):205-18 PubMed

J Pharmacol Exp Ther. 1999 Sep;290(3):1222-9 PubMed

Psychopharmacology (Berl). 1992;108(1-2):196-204 PubMed

Psychopharmacology (Berl). 1993;111(2):144-52 PubMed

Neurosci Biobehav Rev. 1991 Winter;15(4):447-54 PubMed

Eur J Pharmacol. 1998 Oct 2;358(2):117-28 PubMed

Br J Pharmacol. 1975 Sep;55(1):141-50 PubMed

Psychopharmacology (Berl). 1986;90(2):278-80 PubMed

Behav Pharmacol. 1995 Nov;6(7):732-745 PubMed

Pharmacol Biochem Behav. 1999 Apr;62(4):727-34 PubMed

Arch Gen Psychiatry. 1990 Oct;47(10):917-25 PubMed

Psychopharmacology (Berl). 1999 Feb;142(1):85-94 PubMed

Brain Res Bull. 1988 May;20(5):603-6 PubMed

Anesthesiology. 1993 Dec;79(6):1183-92 PubMed

Life Sci. 1991;49(5):325-44 PubMed

Brain Res. 1991 Aug 23;557(1-2):167-76 PubMed

J Neurochem. 1992 Jun;58(6):2102-15 PubMed

Biol Psychiatry. 1999 Feb 1;45(3):321-6 PubMed

Neuropharmacology. 1982 Oct;21(10):1033-7 PubMed

Behav Pharmacol. 2000 Apr;11(2):143-51 PubMed

Neuropharmacology. 1991 Dec;30(12B):1387-9 PubMed

Psychopharmacology (Berl). 1986;89(4):395-403 PubMed

Psychopharmacology (Berl). 1976 Dec 21;51(1):75-80 PubMed

Proc Natl Acad Sci U S A. 1986 Feb;83(3):827-31 PubMed

Psychopharmacology (Berl). 1986;89(1):113-7 PubMed

Neuroscience. 1993 Dec;57(3):777-86 PubMed

Psychopharmacology (Berl). 2001 Apr;154(4):327-35 PubMed

Pharmacol Biochem Behav. 1993 Sep;46(1):161-5 PubMed

Physiol Behav. 2001 Nov-Dec;74(4-5):621-8 PubMed

Psychopharmacology (Berl). 2000 Jan;148(1):24-32 PubMed

Pharmacol Biochem Behav. 1985 Jul;23(1):17-20 PubMed

Acta Anaesthesiol Scand. 1990 Nov;34(8):628-31 PubMed