Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A

Mice deficient in monoamine oxidase A (MAO A) have elevated brain levels of 5-HT and manifest enhanced aggression. We used these mice as a model to study the role of 5-HT in aggression. Our results show that ketanserin and tetrabenazine (TBZ) strikingly abolished the aggressive behavior of MAO A-deficient mice. The anti-aggressive effect of ketanserin may be primarily mediated by 5-HT2A receptors. Another specific 5-HT2A antagonist, [R-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(3-fluorophenylethyl)]-4-piperidine-methanol (MDL 100907), also blocks the aggression of mutant mice but was less dramatic. Ketanserin and TBZ are both antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive effect of TBZ and part of the effect of ketanserin may be mediated by the VMAT2. Using radioligand binding and autoradiography, we also showed that the numbers of VMAT2, 5-HT1A, 5-HT2A and 5-HT2C sites are decreased in brains of mutant mice, which may reflect down-regulation by excess 5-HT. This study suggests that ketanserin and TBZ may be developed as novel anti-aggressive agents. (C) 1999 Elsevier Science B.V, All rights reserved.