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

Abstract

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 Ca 2+, 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.