Impaired nitric oxide synthase signaling dissociates social investigation and aggression

Behav Neurosci. 2007 Apr;121(2):362-9. doi: 10.1037/0735-7044.121.2.362.


A combination of social withdrawal and increased aggression is characteristic of several mental disorders. Most previous studies have investigated the neurochemical bases of social behavior and aggression independently, as opposed to how these behaviors are regulated in concert. Neuronal nitric oxide synthase (nNOS) produces gaseous nitric oxide, which functions as a neurotransmitter and is known to affect several types of behavior including mating and aggression. Compared with wild-type mice, we observed that nNOS knockout mice showed reduced behavioral responses to an intruder behind a wire barrier. Similar results were observed in mice treated with the selective nNOS inhibitor 3-bromo-7-nitroindazole (3BrN). In habituation-dishabituation tests, treatment with 3BrN did not block recognition of male urine but did attenuate investigation time compared with oil-treated animals. Finally, nNOS knockout mice and 3BrN treated mice were significantly more aggressive than wild-type and oil-treated males, respectively. In general, these behavioral effects are less pronounced in pair-housed males compared with singly-housed males. Thus, nNOS inhibition results in a phenotype that displays reduced social investigation and increased aggression. These data suggest that further study of nNOS signaling is warranted in mental disorders characterized by social withdrawal and increased aggression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aggression / physiology*
  • Animals
  • Corticosterone / blood
  • Indazoles / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motivation
  • Nitric Oxide Synthase / physiology*
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / genetics
  • Signal Transduction / physiology*
  • Social Behavior*
  • Testosterone / blood


  • 3-bromo-7-nitroindazole
  • Indazoles
  • Testosterone
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Corticosterone