Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists

Abstract

Rationale: Positive modulators of the benzodiazepine/GABA(A) receptor complex can heighten aggressive behavior; the GABA(A)/alpha(1) subunit may play a critical role in benzodiazepine-modulated aggressive behavior.

Objective: The carboline derivatives, beta-CCt and 3-PBC, antagonists with preferential action at the GABA(A) receptors with alpha(1) subunits, may antagonize benzodiazepine-heightened aggression, thus implicating the alpha(1) subunit in heightened aggression.

Methods: The GABA(A) 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 beta-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 GABA(A) 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. beta-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 GABA(A) gamma and alpha(1) subunits in benzodiazepine-heightened aggression.