Neuronal nitric oxide synthase and affective disorders

Abstract

Affective disorders including major depressive disorder (MDD), bipolar disorder (BPD), and general anxiety affect more than 10% of population in the world. Notably, neuronal nitric oxide synthase (nNOS), a downstream signal molecule of N-methyl-D-aspartate receptors (NMDARs) activation, is abundant in many regions of the brain such as the prefrontal cortex (PFC), hippocampus, amygdala, dorsal raphe nucleus (DRN), locus coeruleus (LC), and hypothalamus, which are closely associated with the pathophysiology of affective disorders. Decreased levels of the neurotransmitters including 5-hydroxytryptamine or serotonin (5-HT), noradrenalin (NA), and dopamine (DA) as well as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are common pathological changes of MDD, BPD, and anxiety. Increasing data suggests that nNOS in the hippocampus play a crucial role in the etiology of MDD whereas nNOS-related dysregulation of the nitrergic system in the LC is closely associated with the pathogenesis of BPD. Moreover, hippocampal nNOS is implicated in the role of serotonin receptor 1 A (5-HTR1 A) in modulating anxiety behaviors. Augment of nNOS and its carboxy-terminal PDZ ligand (CAPON) complex mediate stress-induced anxiety and disrupting the nNOS-CAPON interaction by small molecular drug generates anxiolytic effect. To date, however, the function of nNOS in affective disorders is not well reviewed. Here, we summarize works about nNOS and its signal mechanisms implicated in the pathophysiology of affective disorders. On the basis of this review, it is suggested that future research should more fully focus on the role of nNOS in the pathomechanism and treatment of affective disorders.

Acupuncture at Gastric Back‐Shu and Front‐Mu Acupoints Enhances Gastric Motility via the Inhibition of the Glutamatergic System in the Hippocampus

“…In addition, glutamatergic signalling in the dorsal motor nucleus of the vagus (DMV) via the activation of N-methyl-daspartate receptors (NMDAR) increases gastric motility [17]; NMDAR is widely distributed in the hippocampus [18]. e stimulation of NMDARs results in calcium influx, the activation of neuronal nitric oxide synthase (nNOS), and an increase in the content of nitric oxide (NO) [19,20]. NO plays an important role in regulating gastrointestinal motility, and most of the physiological processes of NO result from its activation of soluble guanylate cyclase (sGC), an enzyme that catalyses the generation of cyclic guanosine monophosphate (cGMP) [21][22][23].…”

Efficacy and Underlying Mechanism of Acupuncture in the Treatment of Posttraumatic Stress Disorder: A Systematic Review of Animal Studies

“…Specifically a study found that EA regulated the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-4 in the hypothalamus of the PTSD animal model [ 38 ]. Moreover, for the locus coeruleus, which plays an important role in stress responsiveness as a nucleus in the brainstem [ 52 ], one study reported that EA can reduce excessive stress responses of PTSD model by downregulating nitric oxide synthase (nNOS) expression in this region [ 31 ]. Finally, one study [ 29 ] reported upregulation of hippocampal mineralocorticoid receptor expression and downregulation of hippocampal glucocorticoid receptor expression after EA.…”

nNOS‐CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety

“…nNOS is the main NOS in the hippocampus, differing from its isoenzymes inducible NOS (iNOS) and endothelial NOS (eNOS) in its PDZ domain, which can interact with many adapter proteins and thus affect its physiological functions (Zhou & Zhu, 2009). An increasing number of reports indicate that nNOS is involved in many pathological conditions, such as anxiety, depression and Alzheimer's disease (Hu et al, 2012; Zhang et al, 2010; Zhou et al, 2007; Zhou et al, 2011; Zhou, Zhu, Nemes, & Zhu, 2018; Zhu et al, 2014; Zhu et al, 2018). Among the adapter proteins of nNOS, other researchers and ourselves have found that CAPON is related to emotional diseases (Brzustowicz, 2008; Delorme et al, 2010; Lawford et al, 2013; Xu et al, 2005; Zhu et al, 2014; Zhu et al, 2018).…”