Elimination of aggressive behavior in male mice lacking endothelial nitricoxide synthase

Male mice with targeted deletion of the gene encoding the neuronal isoform of nitric oxide synthase (nNOS(-/-)) display increased aggressive behavior compared with wild-type (WT) mice. Specific pharmacological inhibition of n NOS with 7-nitroindazole also augments aggressive behavior. We report here that male mice with targeted deletion of the gene encoding endothelial NOS (eNOS(-/-)) display dramatic reductions in aggression. The effects are sele ctive, because an extensive battery of behavioral tests reveals no other de ficits. In the resident-intruder model of aggression, resident eNOS(-/-) ma les show virtually no aggression. Latency for aggression onset is 25-30 tim es longer in eNOS(-/-) males compared with WT males in the rare instances o f aggressive behaviors. Similarly, a striking lack of aggression is noted i n tests of aggression among groups of four mice monitored in neutral cages. Although eNOS(-/-) mice are hypertensive (similar to 14 mmHg blood pressur e elevation), hypertension does not appear responsible for the diminished a ggression. Reduction of hypertension with hydralazine does not change the p revalence of aggression in eNOS(-/-) mice. Extensive examination of brains from eNOS(-/-) male mice reveals no obvious neural damage from chronic hype rtension. In situ hybridization in WT animals reveals eNOS mRNA in the brai n associated exclusively with blood vessels and no neuronal localizations. Accordingly, vascular eNOS in the brain appears capable of influencing beha vior with considerable selectivity.