The effects of N-methyl-citalopram (NMC) on serotonergic systems and antidepressant-like behavior

Depression is projected to be the 2nd leading cause of disability adjusted life years by 2020. Current forms of treatment come in the form of drugs that target monoaminergic systems, for example selective serotonin reuptake inhibitors (SSRIs), which elicit their effects through unknown mechanisms. The mechanisms, if better understood, could improve treatment efficacy and reduce side effects of SSRI drugs in depressed patients. Prior research from our lab has revealed that an ancient thermoregulatory peripheral spinoparabrachial pathway, which projects to serotonergic neurons in the brain, may be defective in depressed patients. We predicted that restoration of this pathway would reduce depression-like symptoms. In this study we tested the hypothesis that N-methyl-citalopram (NMC), a novel compound that does not appear to cross the blood-brain barrier, would produce antidepressant-like behavior in rats through peripheral activation of the spinoparabrachial pathway projecting to the brain. Rats received injections of varying dosages of NMC or a saline control and were then introduced to forced swim testing. Afterwards rat brains were removed and prepared for immunohistochemical detection of the immediate-early gene c-Fos (as a marker for neuronal activation) and TPH (a marker for serotonergic neurons). Our data suggest that NMC increased expression of the immediate-early gene, c-Fos, within serotonergic neurons in specific subregions of the dorsal raphe nucleus (DR); a region shown to have dense populations of serotonergic neurons that project to forebrain limbic structures implicated in the pathophysiology of major depression. Therefore, it is apparent that NMC has implications for antidepressant-like effects, likely through peripheral activation of the spinoparabrachial pathway projecting to the dorsal raphe nucleus. This suggests a novel therapeutic alternative to currently used, centrally acting SSRI treatments