Research reportKetanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A
Introduction
Monoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines in the brain and peripheral tissues with the production of hydrogen peroxide 43, 46. Two forms of MAO have been defined and are designated MAO A and B 23, 24. MAO A has higher affinity for the substrates serotonin (5-HT) and norepinephrine (NE), and the inhibitor clorgyline, whereas MAO B has higher affinity for phenylethylamine, benzylamine and the inhibitor deprenyl. MAO A and B are encoded by different genes 3, 20and are both located on the X-chromosome [27]. Mice deficient in MAO A have elevated brain levels of 5-HT and NE and manifest a distinct behavioral syndrome which includes enhanced aggression in males 8, 44. This is consistent with the impulsive aggression reported in men from a Dutch kindred with a MAO A deficiency, due to a point mutation of the gene 5, 6. We used MAO A-deficient mice as a model to study the role of 5-HT in aggression. Most studies suggest that low brain 5-HT concentrations are associated with enhanced aggression since reduced concentrations of the 5-HT metabolite, 5-hydroxyindolacetic acid, in the cerebrospinal fluid have been correlated with aggressive behavior in humans 10, 31, 33and 5-HT receptor agonists reduce aggression 36, 40, 45. On the other hand, elevated levels of 5-HT in the blood have been correlated with aggressive behavior in humans 4, 11, 32, 34, 37, 47.
There is no medication that is approved by the Food and Drug Administration for the treatment of aggression. Current medications, including benzodiazepines and antipsychotics, treat aggression by sedating the patient [30]. This is the first study to show that ketanserin and tetrabenazine (TBZ) abolish aggression without causing sedation.
Section snippets
Mice
Adult male MAO A KO mice aged 1–2 months were used in all studies. The mice were housed individually and were allowed free access to food and water. They were housed under controlled conditions of temperature (20°–22°C) and humidity (50–60%) in an air-conditioned unit. Lighting was maintained on a 12-h light–dark cycle (lights on 0600–1800 h).
Resident–intruder confrontations
All mice were housed individually for at least 1 week in transparent Makrolon cages measuring 29 cm×13 cm×13 cm. Confrontations were organized in a Latin
The effect of ketanserin, MDL 100907 and TBZ on aggression
The effect of ketanserin on aggression was remarkable. Ketanserin produced a dose-dependent decrease in the aggressive behavior of mutant mice (Fig. 1). The aggression of MAO A-deficient mice was completely abolished by 3 mg/kg ketanserin (P<0.01). Ketanserin had no effect on non-social, investigative, defensive or locomotive behaviors. Since a decrease in locomotion reflects sedation, these data suggest that sedation was not caused by doses of ketanserin which abolished aggression.
Although
Discussion
This is the first study to demonstrate that ketanserin abolishes aggressive behavior. Ketanserin increases footshock-induced aggression in rats [12], but it is ineffective in aggression induced by food competition in pigeons [16]and its effect in aggression when mice were kept isolated for at least three weeks is inconsistent [40]. Our finding that ketanserin abolishes aggression more potently than MDL 100907 contrasts with their affinities for the 5-HT2A receptor where the KD value for [
Acknowledgements
The support by grants from the National Institute for Mental Health (R37 MH39085, Merit Award; K05 MH00795, Research Scientist Award; RO1 MH37020, and the Boyd and Elsie Welin Professorship Award) is greatly appreciated. We are grateful to Dr. B. Roth for the supply of MDL 100907.
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