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Chronic unpredictable stress regulate hippocampal quinolinic acid on rat glutamic acid and its receptor

Author: ChenHuiBin
Tutor: AnShuCheng
School: Shaanxi Normal University
Course: Physiology
Keywords: depression hippocampus NMDAR mGluR1 QUIN glutamate
CLC: R749.4
Type: Master's thesis
Year: 2013
Downloads: 35
Quote: 0
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Abstract


Depressive disorder is a long term, relapsing condition associated with high levels of disability and mortality. It has a neurobiological basis and is associated with functional and structural brain abnormalities which led to abnormality of behavior and emotion of human.The burden of depression has increased, as the prevalence of current depression. Therefore, it is particularly important to find out the pathogenesis of depression as soon as possible. Extensive literatures have shown that depression is caused by a deficiency of serotonin (5-HT), and part of the current antidepressant pharmacological treatments are inspired by it. Nonetheless,5-HT depletion cannot fully explain the whole performance of depression. At present, a large number of studies have improved that stress is the crucial part in depression. The stress leads to Glu in hippocampus increased and NMDA receptors acted excessively. NMDA receptor antagonists have a significant effect of antidepressant. Furthermore, the expression of metabolic glutamic acid receptor1(mGluR1) have also increased in rat hippocampus by stress and the antagonists of mGluRl have remarkable effect of antidepressant which caused by stress. Quinolinic acid (QUIN) is a downstream product of the kynurenine pathway which shares TRP with the5-HT pathway. It is another main TRP metabolic pathway. QUIN, act as an NMDA receptor agonist, is only produced by activated microglia within the brain. QUIN may be involved in many psychiatric disorders, neurodegenerative processes in the brain, as well as other disorders. There is high level of3-hydroxykynurenine (3HK) which can lead to produce QUIN in urinary excretion of depressive patient. Therefore, tryptophan metabolism disorder led to a decline in5-HT and the rise of QUIN probably is related with depression. And metabolic abnormalities in tryptophan will reduce5-HT and increase QUIN. When QUIN is at pathological concentrations, it not only can lead to nerve damage through NMDA receptor and metabolic glutamic acid receptor respectively, but also restrain the expression of glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle occurs, which cause intensified toxic effect of QUIN. Lots of the research in depression mechanism have focused on the change of5-HT, the role of QUIN in stress-induced depression still unclear.For its specialty, hippocampus is one of important region in depression. However, it is still unclear that whether the QUIN has associated with stress-induced depression-like behavior and whether the change of animals’ emotion and behavior have relation to the Glu,NMDA receptor and mGluRl in the hippocampus. The present study was to investigate the role of QUIN which was released by activated microglia in hippocampus and the relationship between QUIN, NMDA receptor and mGluRl in depression induced by chronic unpredictable mild stress (CUMS). CUMS-induced depression model was established. The behaviors were conducted by measurement of weight changes, sucrose preference test, open-field test, and tail suspension test. Intrahippocampal microinjection of QUIN, QUIN antagonist Ro61-8048, NMDA receptor blocker MK-801and mGluR1blocker AIDA was performed under stereotaxic guide cannula. The expression of QUIN was detected by ELISA. The expression of Glu and its receptors’ subunits were detected respectively by HPLC and Western blot.The result showed that CUMS significantly induced the depressive-like behaviors in rats. The content of QUIN and Glu, the expression of NMDA receptors’ subunits NR2B and mGluRl had increased significantly in the hippocampus in comparison with the control group. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors and the content of Glu had added, the expression of NR2B and mGluRl had increased significantly. QUIN antagonist Ro61-8048had effectively restrained the depression-like behaviors induced by CUMS, and the expression of NR2B and mGluRl had decreased significantly. Intrahippocampal injections of MK-801and AIDA had effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content.The results indicate that the CUMS can cause increased release of QUIN in hippocampus which led to a high expression of NR2B and mGluR1, and that caused increased level of Glu. High levels of Glu produce nerve excitability toxicity which have led to depression.

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CLC: > Medicine, health > Neurology and psychiatry > Psychiatry > Affective psychosis
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