- Alterations of nitric oxide (NO) metabolism in the brain have been associated with modifications of stress-related behavior in animal models. It has been generally assumed that these behavioral changes are due to the neuronal nitrosative activity. On the other hand, glial NO production has been demonstrated mainly as a slow reaction to brain insults through the activity of an inducible nitric oxide synthase (NOS) isoform (NOS2). Recently we uncovered increased NOS activity in astrocytes of mice with a NOS2 mutation. Interestingly, these mice revealed a behavioral phenotype suggestive of increased susceptibility to stress. In the present study we investigated the responses of these mutants to stress by exposing them to predator scent. Seven days later, mutant mice exhibited significantly higher anxiety-like behavior in the elevated-plus maze, increased acoustic startle responses, and higher plasma corticosterone levels compared with their controls. Systemic administration of a NOS inhibitor prior to the stress exposure reversed these stress-related effects without affecting controls' behavior. These findings are in agreement with previous studies showing an association between increased NO levels and enhanced anxiety-like responses. In addition, mutant mice performed better in the Morris water maze prior to stress exposure, but the two animal groups performed alike in an object-recognition test. Taken together, our results suggest the involvement of astrocytic-derived NO in modulating behavior.