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-HT(2A) receptors. Another specific 5-HT(2A) antagonist, [R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methan ol (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-HT(1A), 5-HT(2A) and 5-HT(2C) 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.
Shih
J C
JC
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Room 528, 1985 Zonal Avenue, Los Angeles, CA 90033, USA. jcshih@hsc.usc.edu
Ridd
M J
MJ
Chen
K
K
Meehan
W P
WP
Kung
M P
MP
Seif
I
I
De Maeyer
E
E
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000374:Aggression / Q000187:drug effects*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005464:Fluorobenzenes / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013747:Tetrabenazine / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D005464:Fluorobenzenes; D018377:Neurotransmitter Agents; D010880:Piperidines; D012702:Serotonin Antagonists; D007650:Ketanserin; D008995:Monoamine Oxidase; C079049:volinanserin; D013747:Tetrabenazine