Chronic inflammation disturbs regulation of serotonin transporter in major depression: intracellular mechanism
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Major depression is a complex neuropsychiatric disorder which is becoming a world wide health problem. Several studies indicate that chronic inﬂammation or chronic psychosocial stress can induce, or at least con- tribute to, major depression. In this review the precise molecular pathway of p38 MAPK in which chronic stress can eventually cause depression is discussed, with a synergistic role for proinﬂammatory cytokines. We propose a mechanism in which chronic stress acts on the adrenergic pathway, activating the p38 MAPK and eventually increase the activity and afﬁnity of the serotonin transporter leading to a decrease of serotonin in the synapse. In addition, proinﬂammatory cytokines present due to systemic inﬂammation or peripheral inﬂammation, provide a positive feedback loop resulting in a chronic state of inﬂammation. Proinﬂammatory cytokines can also activate the adrenergic system and thereby creating a synergistic effect combined with chronic psychosocial stress resulting again in serotonin transporter disfunctioning. Alterations in the seroto- nergic system are known to have wide spread behavioral effects, which could lead to depression-like features. Furthermore, future research prospectives, new treatments possibilities and additional monitoring options are discussed. The serotonergic system is implicated in many psychiatric diseases, other than depression, such as schizophrenia, obsessive compulsive disorder and autism. Therefore, the clear overview of the p38 path- way described in this review can contribute to the overall knowledge of many more psychiatric disorders. Furthermore, the new research, therapeutic and monitor options could also be of relevance to, in addition to depression, these psychiatric disorders.