Elsevier

Brain Research

Volume 835, Issue 2, 24 July 1999, Pages 104-112
Brain Research

Research report
Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A

https://doi.org/10.1016/S0006-8993(99)01478-XGet rights and content

Abstract

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-(4-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.

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 [3H

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.

References (47)

  • B. Olivier et al.

    Rodent models of aggressive behavior and serotonergic drugs

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1992)
  • S.R. Pliszka et al.

    Plasma neurochemistry in juvenile offenders

    J. Am. Acad. Child Adolesc. Psychiatry

    (1988)
  • A.S. Unis et al.

    Platelet serotonin measures in adolescents with conduct disorder

    Biol. Psychiatry

    (1997)
  • S.P.H. Alexander, J.A. Peters, Receptor and ion channel nomenclature supplement, TIPS Suppl. (1997)...
  • A.W. Bach et al.

    cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties

    Proc. Natl. Acad. Sci. USA

    (1988)
  • C.S. Brown et al.

    Blood platelet uptake of serotonin in episodic aggression

    Psychiatry Research

    (1988)
  • H.G. Brunner et al.

    Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A

    Science

    (1993)
  • H.G. Brunner et al.

    X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism

    Am. J. Hum. Genet.

    (1993)
  • O. Cases et al.

    Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs

    J. Neurosci.

    (1998)
  • O. Cases et al.

    Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAO A

    Science

    (1995)
  • J.N. Constantino et al.

    CSF 5-HIAA and family history of antisocial personality disorder in newborns

    Am. J. Psychiatry

    (1997)
  • K.P. Datla et al.

    Serotonergic modulation of footshock-induced aggression in paired rats

    Indian J. Exp. Biol.

    (1991)
  • B.S. Eichelman et al.

    The aggressive monoamines

    Biol. Psychiatry

    (1973)
  • Cited by (73)

    • Serotonin and aggression—an update

      2020, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      It is likely that the change of 5-HT function is the cause of the behavioral changes in the MAOA-deficient mice. Ketanserin and MDL100907, antagonists that preferentially bind to 5-HT2A, blocked the escalated aggression in the MAOA mutant mice (Shih et al., 1999). Depletion of 5-HT by PCPA during the early developmental stage improved some behavioral and brain structural abnormality in the MAOA-deficient mice (Cases et al., 1995, 1996).

    • Serotonin and aggression

      2019, The Serotonin System: History, Neuropharmacology, and Pathology
    • Methylphenidate-risperidone combination in child psychiatry: A retrospective analysis of 44cases

      2014, Annales Pharmaceutiques Francaises
      Citation Excerpt :

      For instance, preclinical data show the importance of serotonin and dopamine through their action on 5HT1A/B, 5HT2A and D2 receptors [74]. These experiments have established that antagonists of the 5HT2A receptors, such as ritanserin or ketanserin, reduce aggression, while their agonists have opposite effects [75,76]. Similarly the D2 receptor antagonists such as tiapride or spirenone, reduce aggression, contrary to their agonists [77,78].

    • Serotonin receptor 6 mediates defective brain development in monoamine oxidase A-deficient mouse embryos

      2014, Journal of Biological Chemistry
      Citation Excerpt :

      These data suggest that elevated 5-HT levels contribute to the developmental defects induced by MAO-A expression silencing. 5-HT exerts its biological functions by binding to a class of 5-Htrs, and 5-Htr-1a, -1b, and -2 subtypes have been implicated previously in abnormal perinatal maturation of neuronal structures of MAO-A-deficient mice (26–28). However, the roles of these receptor isoforms during early embryo development have not been explored in detail.

    • Monoamine oxidase A and A/B knockout mice display autistic-like features

      2013, International Journal of Neuropsychopharmacology
    View all citing articles on Scopus
    View full text