Nitric oxide signalling and antidepressant action revisited

Abstract

Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.

Repeated Nitrous Oxide Exposure Exerts Antidepressant-Like Effects Through Neuronal Nitric Oxide Synthase Activation in the Medial Prefrontal Cortex

“…NO is a gaseous neurotransmitter that governs multiple physiological functions in the CNS. NO is synthesized by NOS, which has three isoforms, namely, nNOS, iNOS, and eNOS, and all three NOS isoforms exist in the CNS and affect cell signaling in brain (29). Evidence has shown that deficits in NOS activity are associated with the neurobiology of MDD (30,31).…”

“…Evidence has shown that deficits in NOS activity are associated with the neurobiology of MDD (30,31). Especially for nNOS, studies have shown that dysfunction of nNOS in the paraventricular hypothalamic nucleus, locus coeruleus, mPFC, and hippocampus, is related to MDD (29,32,33). Besides, iNOS also is involved in stress-triggered depression, as iNOS derived NO and iNOS mRNA levels increased in the cortices of depression animal model (34).…”

Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

“…Acute stress triggers a complex response involving the synthesis and release of mediators such as corticoids, glutamate and NO, which can acutely alter gene expression as well as induce long-term molecular and behavioral changes (Popoli et al, 2011;Joca et al, 2019). The increase in NO and/or reactive oxygen species (ROS) can directly impact gene expression (Riccio et al, 2006;Lee et al, 2009;Nott & Riccio, 2009).…”

Chaperone Sigma1R and Antidepressant Effect

“…NO plays an important role in the mechanisms of neuroplasticity and the neurobiology of depression. Therefore, maintaining NO signaling, counteraction of NO overproduction, and oxidative damage may be essential factors in antidepressant therapy [209]. In a model of depression induced by estrogen withdrawal (E2) under hormone-stimulated pregnancy, an increase in the immobilization time in the forced swim test and tail suspension test of ICR mice was combined with a decrease in the levels of nNOS, NO, and p-CREB in the hippocampus.…”