Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists.
BACKGROUND
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.
Department of Psychology, Tufts University, 530 Boston Ave. (Bacon Hall), Medford, MA 02155, USA.
Shannon L
SL
Gourley
Joseph F
JF
Debold
Wenyuan
W
Yin
James
J
Cook
Klaus A
KA
Miczek
D000374:Aggression / Q000187:drug effects*; D000378:Agonistic Behavior / Q000187:drug effects; D000818:Animals; D001143:Arousal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000187:drug effects; D014229:Triazolam / Q000494:pharmacology*
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D014229:Triazolam; D008874:Midazolam