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Lowering/Decreasing Nitric Oxide increases Aggressive Behavior

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Inhibition of neuronal nitric oxide synthase increases aggressive behavior in mice.
G. E. Demas, M. J. Eliasson, T. M. Dawson, V. L. Dawson, L. J. Kriegsfeld, R. J. Nelson, and S. H. Snyder
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BACKGROUND: Mice with targeted disruption of the gene for the neuronal isoform of nitric oxide synthase (nNOS) display exaggerated aggression. Behavioral studies of mice with targeted gene deletions suffer from the criticism that the gene product is missing not only during the assessment period but also throughout development when critical processes, including activation of compensatory mechanisms, may be affected. To address this criticism, we have assessed aggressive behavior in mice treated with a specific pharmacological inhibitor of nNOS. MATERIALS AND METHODS: Aggressive behavior, as well as brain citrulline levels, were monitored in adult male mice after treatment with a specific nNOS inhibitor, 7-nitroindazole (7-NI) (50 mg/kg i.p.), which is known to reduce NOS activity in brain homogenates by > 90%. As controls, animals were treated with a related indazole, 3-indazolinone (3-I) (50 mg/kg i.p.) that does not affect nNOS or with on oil vehicle. RESULTS: Mice treated with 7-NI displayed substantially increased aggression as compared with oil- or 3-I-injected animals when tested in two different models of aggression. Drug treatment did not affect nonspecific locomotor activities or body temperature. Immunohistochemical staining for citrulline in the brain revealed a dramatic reduction in 7-NI-treated animals. CONCLUSIONS: 7-NI augmented aggression in WT mice to levels displayed by nNOS- mice, strongly implying that nNOS is a major mediator of aggression. NOS inhibitors may have therapeutic roles in inflammatory, cardiovascular, and neurologic diseases. The substantial aggressive behavior soon after administration of an nNOS inhibitor raises concerns about adverse behavioral sequelae of such pharmacological agents.

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Nitric oxide (NO) modulates many behavioral and neuroendocrine responses. Genetic or pharmacological inhibition of the synthetic
enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Recently, the excessive aggressive and
impulsive traits of neuronal NO synthase knockout (nNOS/) mice were shown to be caused by reductions in serotonin (5-HT) turnover
and deficient 5-HT1A and 5-HT1B receptor function in brain regions regulating emotion. The consistently high levels of aggression observed
in nNOS/ mice could be reversed by 5-HT precursors and by treatment with specific 5-HT1A and 5-HT1B receptor agonists. The
expression of the aggressive phenotype of nNOS/ knockout mice requires isolated housing prior to testing. The effects of social factors
such as housing condition and maternal care can affect 5-HT and aggression, but the interaction among extrinsic factors, 5-HT, NO, and
aggression remains unspecified. Taken together, NO appears to play an important role in normal brain 5-HT function and may have
significant implications for the treatment of psychiatric disorders characterized by aggressive and impulsive behaviors.
© 2003 Elsevier Inc. All rights reserved.
Keywords: Aggression; Violence; Gene knockout; Mouse; Animal model; Isolation; Environmental factors

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