GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice.
BACKGROUND
The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved.


OBJECTIVE
Beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) and zolpidem act preferentially at GABAA receptors containing the alpha1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression.


METHODS
Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists beta-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period.


RESULTS
Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or beta-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg beta-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation.


CONCLUSIONS
Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.
de Almeida
Rosa M M
RM
Department of Psychology, Tufts University, Bacon Hall, 530 Boston Avenue, Medford, MA 02155, USA.
Rowlett
James K
JK
Cook
James M
JM
Yin
Wenyuan
W
Miczek
Klaus A
KA
D000374:Aggression / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D004357:Drug Synergism; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects; D012646:Self Administration; D000077334:Zolpidem
D002243:Carbolines; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011725:Pyridines; D011963:Receptors, GABA-A; D000431:Ethanol; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate