Elsevier

Psychiatry Research

Volume 85, Issue 1, 18 January 1999, Pages 33-38
Psychiatry Research

Nitric oxide and biopterin in depression and stress

https://doi.org/10.1016/S0165-1781(98)00140-1Get rights and content

Abstract

Depression has been hypothesized to be related to the reduced biosynthesis of neurotransmitters such as serotonin, noradrenalin and dopamine. Much past research has also been devoted to dysregulation of the hypothalamic—pituitary—adrenal (HPA) axis in depression. The present article reviews the evidence linking tetrahydrobiopterin, a co-factor in the biosynthesis of neurotransmitters, and nitric oxide, an apparent neuroendocrine modulator of the HPA axis, to the immune system and to neuronal control within affective disorder and stress. On the basis of this review, it is suggested that future psychoneuroimmunological research should more fully explore the possible role of tetrahydrobiopterin and nitric oxide in depressive disorders.

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      This led to the discovery that increased nNOS expression in hippocampal CA1 and subiculum of BPD patients (Oliveira et al., 2008) and that iNOS mRNA expression and protein levels are increased in postmortem frontal cortex from BPD compared to control subjects (Rao et al., 2010). Although the contribution of NO to MDD was investigated via the effects of methylene blue in MDD patients as early as the 1980 s (Moody et al., 1989; Narsapur and Naylor, 1983; Naylor et al., 1987; Turner, 1985), it wasn’t established until the late 1990 s that brain-derived NO plays an important role in the pathogenesis of depression (Harvey, 1996; Karatinos et al., 1995; van Amsterdam and Opperhuisen, 1999). Some studies of MDD patients demonstrated a significant reduction in the total amount and density of NOS immunoreactive neurons in the paraventricular nucleus (Bernstein et al., 1998), nNOS immunoreactivity in the locus coeruleus (Karolewicz et al., 2004), activity of both eNOS and nNOS in prefrontal cortex (Xing et al., 2002), platelet eNOS activity as well as plasma levels of NO metabolites (NOx) (Chrapko et al., 2004; Ozcan et al., 2004; Selley, 2004) and polymorphonuclear leukocytes NOx levels (Srivastava et al., 2002).

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      NO can also react with cysteine thiol, S-nitrosylation, and transition metal centers for numerous downstream effects (Drapier & Bouton, 1996; Stamler et al., 1992). In the late 1990s and early 2000s, it was hypothesized that central NO has a role in the pathogenesis of depression (Harvey, 1996; Karatinos et al., 1995; van Amsterdam & Opperhuisen, 1999). This hypothesis derived from reports demonstrating a significant reduction in the activity of both eNOS and nNOS in prefrontal cortex (Xing, Chavko, Zhang, Yang, & Post, 2002), platelet eNOS activity or levels of plasma NO metabolites (NOx) (Chrapko et al., 2004; Ozcan, Gulec, Ozerol, Polat, & Akyol, 2004; Selley, 2004), density of NOS immunoreactive neurons in the paraventricular nucleus (Bernstein et al., 1998), nNOS immunoreactivity in the locus coeruleus (Karolewicz et al., 2004) and polymorphonuclear leukocytes NOx levels (Srivastava, Barthwal, Dalal, et al., 2002) in patients with MDD.

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      Nitric oxide synthases are a family of three proteins consisting of endothelial (eNOS), neuronal (nNOS) and inducible NOS (iNOS) which play a modulatory role in biological processes such as cardiovascular regulation and neurotransmission [17]. In this context, eNOS and nNOS are constitutive isoenzymes, which account for generation of low levels of NO, while it has been shown that iNOS is responsible for overproduction of NO mostly under pathological conditions [16]. Previous studies have shown that nitrergic system is involved in the pathogenesis of mood and anxiety disorders [18].

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      Thirdly, interferon α (IFNα), TNF, and IL1β have been shown to upregulate the serotonin transporter (5-HTT) in vitro (Tsao et al., 2006; Zhu et al., 2006), while intraperitoneal administration of double-stranded DNA (which mimics a viral infection) increased expression of IFNα and 5-HTT but decreased extracellular serotonin in the medial prefrontal cortices of mice (Katafuchi et al., 2006). Fourthly, inflammation may lead to a decrease in tetrahydrobiopterin (BH4) which is a cofactor for the production of both serotonin and dopamine (van Amsterdam and Opperhuizen, 1999; Hoekstra et al., 2006). It is not clear what cell types were responsible for the mood disorder-associated differences in gene expression in our study.

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