Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test.

Previous studies have demonstrated that antagonists at the NMDA receptor are as efficacious as tricyclic antidepressants in pre-clinical antidepressant screening procedures and in blocking or reversing the behavioral deficits associated with animal analogs of major depressive symptomatology. The NMDA receptor complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide (NO) synthase. We hypothesized that NO synthase antagonists might display antidepressant-like properties, similar to NMDA receptor antagonists. We examined the effects of N(G)-nitro-L-arginine (L-NNA), its dextrorotatory enantiomer, D-NNA, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) at doses from 1 to 30 mg/kg in the forced swim test in mice. We now report that NO synthase antagonists are as efficacious as imipramine (15 mg/kg) in reducing the duration of immobility in the mouse forced swim test. The effects of NO synthase antagonists, as well as those of imipramine were blocked by pre-treatment with L-arginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO synthase antagonists were without effect on locomotor activity over the dose range active in the forced swim test (3-10 mg/kg). Likewise, L-Arg was without effect on locomotor activity. These data support the hypothesis that NO synthase antagonists possess antidepressant properties and may represent a novel class of therapeutics for major depressive disorders.