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 st udy the role of 5-HT in aggression. Our results show that ketanserin and te trabenazine (TBZ) strikingly abolished the aggressive behavior of MAO A-def icient mice. The anti-aggressive effect of ketanserin may be primarily medi ated by 5-HT2A receptors. Another specific 5-HT2A antagonist, [R-(+)-a-(2,3 -dimethoxyphenyl)-1-[2-(3-fluorophenylethyl)]-4-piperidine-methanol (MDL 10 0907), also blocks the aggression of mutant mice but was less dramatic. Ket anserin and TBZ are both antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive effect of TBZ and part of the effect of ketan serin may be mediated by the VMAT2. Using radioligand binding and autoradio graphy, 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-regul ation by excess 5-HT. This study suggests that ketanserin and TBZ may be de veloped as novel anti-aggressive agents. (C) 1999 Elsevier Science B.V, All rights reserved.