Neuronal Nitric oxide synthase : a novel target for antidepressant activity

Abstract

Major depressive disorder (MDD) is one of the most common psychiatric disorders and its origin has been attributed to dysfunction of the monoamine systems, particularly noradrenergic and serotonergic, making them the main targets of the majority of antidepressants currently available. However a number of unmet clinical needs remain, such as a delay of several weeks from the first treatment to manifest antidepressant effects, low remission rates and high rates of relapse and recurrence. Fast acting antidepressant activity and efficacy in treatment-resistant cases has been reported with drugs that inhibit the glutamate N-methyl-D-aspartic acid (NMDA) receptor. However, this pharmacological approach is problematic, as it leads to motor and psychotic side effects. Inhibitors of nitric oxide synthase (NOS), a downstream target of NMDA receptors, produce antidepressant effects in the Porsolt test of antidepressant activity in laboratory rodents, without the adverse effects associated with NMDA receptor antagonism. Given the role of neuronal NOS (nNOS) is mediating glutamatergic transmission in the brain, this enzyme represents a novel putative target for the development of a faster acting and more efficacious antidepressant treatment. Here the efficacy of nNOS inhibitors in preclinical models of depression is further assessed. Specifically new insights are provided into the role of 5-HT in the antidepressant-related actions of both ketamine and the NOS inhibitor Nw-Nitro-L-arginine (L-NA). L-NA shows antidepressant-related effects in the olfactory bulbectomised (OB) rat model of depression and attenuates the characteristic hyperactivity with a more rapid onset of action when compared to the tricyclic antidepressant imipramine