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Psychopharmacology (Berl). 2005 Mar;178(2-3):232-40. Epub 2004 Aug 17.

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

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



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.


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.


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.


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).


These results implicate both the GABA(A) gamma and alpha(1) subunits in benzodiazepine-heightened aggression.

[Indexed for MEDLINE]

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