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 ar e as efficacious as tricyclic antidepressants in pre-clinical antidepressan t screening procedures and in blocking or reversing the behavioral deficits associated with animal analogs of major depressive symptomatology. The NMD A receptor complex gates Ca2+, which interacts with calmodulin to subsequen tly activate nitric oxide (NO) synthase. We hypothesized that NO synthase a ntagonists might display antidepressant-like properties, similar to NMDA re ceptor 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 im mobility in the mouse forced swim test. The effects of NO synthase antagoni sts, as well as those of imipramine were blocked by pre-treatment with L-ar ginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO synthase anta gonists were without effect on locomotor activity over the dose range activ e 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 a ntagonists possess antidepressant properties and may represent a novel clas s of therapeutics for major depressive disorders. (C) 1999 Elsevier Science B.V. All rights reserved.