HPA and immune axes in stress: involvement of the serotonergic system.
ABSTRACT Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. There is experimental and clinical evidence that the rise in the concentration of pro-inflammatory cytokines and glucocorticoids, which occurs in a chronically stressful situation and also in depression, contributes to the behavioural changes associated with depression. A defect in serotonergic function is associated with these hormonal and immune changes. Neurodegenerative changes in the hippocampus, prefrontal cortex and amygdalae are the frequent outcomes of the changes in the hypothalamic-pituitary-adrenal axis and the immune system. Such changes may provide evidence for the link between chronic depression and dementia in later life.
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ABSTRACT: The increased association between depression and diabetes mellitus is generally acknowledged. Recent studies suggest that depression leads to diabetes. However, the underlying molecular mechanisms for this association remain unclear. Literature and our data indicate that inflammatory and/or stress factors in depression up-regulate tryptophan (TRP) conversion into kynurenine (KYN), a substrate for nicotinamide adenine dinucleotide (NAD) biosynthesis. Deficiency of vitamin B6, a cofactor of the key enzymes of KYN - NAD pathway, shunts KYN metabolism from formation of NAD towards production of xanthurenic (XA) and kynurenic (KYNA) acids. Human and experimental studies reveal that XA, KYNA and their metabolites interfere with production, release and biological activity of insulin. We propose that inflammation- and/or stress-induced up-regulation of TRP - KYN metabolism in combination with vitamin B6 deficiency is one of the mechanisms mediating increased risk of diabetes in depression. Consequently, monitoring formation of diabetogenic KYN derivatives might help to identify subjects-at-risk for the development of diabetes. Pharmacological down-regulation of the TRP - KYN - NAD pathway and maintenance of adequate vitamin B6 status might help to prevent the development of diabetes in depression and other conditions associated with inflammation/stress- induced excessive production of KYN and vitamin B6 deficiency, e.g., obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.Journal of bioinformatics and diabetes. 09/2013; 1(1).
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ABSTRACT: Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development.Journal of psychiatry & neuroscience: JPN 10/2014; 39(5):140099. · 7.49 Impact Factor
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ABSTRACT: Somatic complaints in children and adolescents may be considered part of a broader spectrum of internalizing disorders that include anxiety and depression. Previous research on the topic has focused mainly on the relationship between anxiety and depression without investigating how common somatic symptoms relate to an underlying factor and its etiology. Based on the classical twin design with monozygotic and dizygotic twins reared together, our study aimed to explore the extent to which the covariation between three phenotypes in adolescent girls and boys can be represented by a latent internalizing factor, with a focus on both common and specific etiological sources. A population-based sample of twins aged 12–18 years and their mothers and fathers (N = 1394 families) responded to questionnaire items measuring the three phenotypes. Informants' ratings were collapsed using full information maximum likelihood estimated factor scores. Multivariate genetic analyses were conducted to examine the etiological structure of concurrent symptoms. The best fitting model was an ACE com-mon pathway model without sex limitation and with one substantially heritable (44 %) latent factor shared by the phenotypes. Concurrent symptoms also resulted from shared (25 %) and non-shared (31 %) environments. The factor loaded most on depression symptoms and least on somatic complaints. Trait-specific influences ex-plained 44 % of depression variance, 59 % of anxiety variance, and 65 % of somatic variance. Our results suggest the presence of a general internalizing factor along which somatic complaints and mental distress can be modeled. However, specific influences make the symptom types distinguishable.Journal of Abnormal Child Psychology 01/2015; · 3.09 Impact Factor