Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects

Rationale: Systemic inhibition of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in rodents. The mechanisms and brain regions mediating this effect are still unknown. The hippocampus is a brain region proposed to mediate adaptation to stress and antidepressant behavioral effects. Therefore, it could be involved in the antidepressant effects of NOS inhibitors. Objectives: To test the hypothesis that nNOS inhibition in the dorsal hippocampus will induce antidepressant-like effects in the forced swimming test (FST) in rats. Methods: Rats implanted with cannulas aimed at the dorsal hippocampus were submitted to 15 min of forced swimming (pretest). Immediately before or after pretest they received bilateral microinjections of the nNOS inhibitor 7-nitroindazole (7-NI; 50, 100, or 200 nmol/0.5 mu l) or vehicle, alone or combined with L-arginine. Additional groups received SIN-1 (125 or 250 nmol/0.5 mu l), a NO donor, either before or after the pretest. Twenty-four hours later, immobility time was registered for 5 min in the FST. Results: 7-NI (100 nmol) significantly decreased immobility time when administered either before or after pretest. Pretreatment with L-arginine (100 nmol/0.5 mu l) prevented these effects but produced no significant effects per se. SIN-1 did not induce any significant effect. Conclusions: These data suggest that the reduction of NO levels within the hippocampus can induce antidepressant-like effects; thus implicating endogenous hippocampal NO in the neurobiology of stress and depression.