Immune changes and neurotransmitters: possible interactions in depression?

Abstract

A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

Keywords: 5,6,7,8-tetrahydrobiopterin; 5-HT; BH(4); DA; Depression; Dopamine; GCH; GTP cylohydrolase I; HIV; HUVEC; IDO; IFN-α -ß -γ; Inflammation; Interferon-γ; Kyn/Trp; LPS; NA; NET; NO; O(2)(−); ONOO(−); Oxidative stress; PAH; PKU; Phe/Tyr; Phenylalanine; ROS; Serotonin; TDO; TNF-α; Tetrahydrobiopterin (BH4); human immunodeficiency virus infection; human umbilical vein endothelial cells; indoleamine 2,3-dioxygenase; interferon-α, -ß, -γ; kynurenine to tryptophan ratio; l-3,4-dihydroxyphenylalanine; l-DOPA; lipopolysaccharide; nitric oxide; noradrenaline; norepinephrine transporter; peroxinitrite; phenylalanine 4-hydroxylase; phenylalanine to tyrosine ratio; phenylketonuria; reactive oxygen species; superoxide anion; tryptophan 2,3-dioxygenase; tumor necrosis factor-α.