Effects of nitric oxide on the HPA axis and aggression

We previously documented that male mice lacking the gene encoding the neuronal isoform of nitric oxide synthase (nNOS-/-) are more aggressive than wildtype (WT) mice in all standard testing paradigms. Testosterone is necessary, but not sufficient, to evoke the persistent aggression in these mutants. Deletion of the nNOS gene not only eliminates nNOS protein, but in common with many gene deletions, affects several 'down-stream' processes. For example, serotonin (5-HT) metabolism is altered in male nNOS-/- mice. Baseline corticosterone, but not ACTH, concentrations are also altered in the nNOS-/- mice. Despite elevated corticosterone concentrations, nNOS knockout mice are less 'anxious' or 'fearful' than WT mice, which may contribute to their aggressiveness. For example, male nNOS-/- mice spend more time in the open field than WT mice. Furthermore, nNOS knockout mice also show increased sensitivity to painful stimuli, which may also prolong aggressive interactions. Aggressive behaviour is not a unitary process, but is the result of complex interactions among several physiological, motivational, and behavioural systems, with contributions from the social and physical environment. The multiple, and often unanticipated, effects of targeted gene disruption on aggressive behaviour are discussed.