Regional specific modulation of neuronal activation associated with the antidepressant-related properties of neuronal nitric oxide synthase (nNOS) inhibitors

Abstract

Depression is a significant health problem in today’s society and when left untreated can be a devastating illness. Current antidepressant treatments are far from ideal as several weeks are required for a therapeutic effect, and up to 30% of patients do not respond to currently available treatments. 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. It has recently been shown that inhibitors of neuronal nitric oxide synthase (nNOS), a down stream target of NMDA receptors, produce antidepressant effects in the Porsolt test (FST) of antidepressant activity in rats and mice, without the adverse effects associated with NMDA receptor antagonism. Given the role of nNOS in mediating glutamatergic transmission in the brain, this enzyme represents a novel target for the development of a faster acting and more efficacious antidepressant treatment. Here we assess the efficacy of selective nNOS inhibitors in more sophisticated pre-clinical models of depression. Specifically, this project assessed the efficacy of the nNOS inhibitors L-NA, TRIM and ZL006 in a combined 5-HT depletion and stress rat model of depression and in the WKY rat, a genetically predisposed rat to anxiety and depression-related behaviour. Subsequently, the effects of these test compounds were examined for changes in FST-induced expression of the immediate early gene (IEG) c-FOS, used to map neuronal activation, to determine brain regions involved in mediating the antidepressant-related effects in the Porsolt test.