On aggression

To better understand the role of nitric oxide in brain function and behavior, researchers at Johns Hopkins University School of Medicine (Baltimore) inactivated the mouse gene for neuronal nitric oxide synthase (nNOS). The resulting null mice (nNOS -/-) showed various physical and behavioral abnormalities, but perhaps the most dramatic change was in their aggressive behavior. In short, the male null mice were prone to kill each other. The chemical inhibition of nNOS in wild-type male mice led to similar behavior. Thus, it was obvious that nitric oxide mediated the behavioral changes, but how?

Previous aggression studies had largely focused on the serotonergic system. Studies in humans and rodents showed that increased levels of serotonin (5-hydroxytryptamine, 5-HT) metabolites, a sign of increased 5-HT turnover, were associated with decreased aggression.This behaviorwas also witnessed with the pharmacological stimulation of 5-HT neurotransmission and the application of 5-HT receptor agonists.Recent work by the Hopkins groups suggests a tangible link connecting nNOS with 5-HT and its receptors(Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 1277–1281).

By determining the ratio of 5-HT to one of its metabolites, 5-hydroxyindole-3-acetic acid, the researchers noted a reduction in 5-HT turnover in the brains of nNOS -/- mice as compared to their wild-type brethren. Furthermore, when wild-type and mutant mice were treated with a precursor of 5-HT that increases 5-HT and 5-HIAA levels and facilitates 5-HT turnover, aggression in mutant mice fell dramatically. Similarly, injections of an inhibitor of 5-HT synthesis given to mutant and wild-type mice on each of three days before the testing led to profoundly reduced 5-HT levels and turnover in both populations; but these findings were associated with increased aggression only in wild-type mice.

To determine whether the nNOS mutation affected the function of 5-HT receptors, the researchers studied the effects of receptor agonists on aggression. Agonists for either of the 5-HT receptorsreduced aggression in both populations, but approximately 2- to 4-fold higher doses of either agonist were required to achieve the same effect in the nNOS -/- mice as in the wild-type mice. This result suggested functional alterations in the receptors of the nNOS -/- population.

The authors believe that linking the two signaling pathwaysmay have “implications for the treatment of psychiatric disorders characterized by aggressiveness and impulsivity.”