Chronic Stress, Depression And Hippocampal Glu And Gaba Levels And Its Receptor Mechanism

Depression is a syndrome mainly characterized by long-lasting low mood and anhedonia. Along with fast development, fierce competition and much more pressure from life and work in recent years, the incidence of depression is increasing year by year. Own to its high incidence, high suicide ratio, heavy economical load, easy palindromia and automutiation, depression has become one of the most harmful psych-emotion disorders.However, the pathogenesis mechanism of depression is still complex and uncovered.y-aminobutyric acid (GABA) is the most crucial inhibitory neurotransmitter in mammal central nervous system, which almost inhibits all the neurons. Recent researches demonstrate the dysfunction of GABA-ergic system is the principal feature in schizophrenia, anxiety disorder and bipolar disorder etc, indicating that GABA play an important role in emotion disorders. And also, GABA decreases in cerebrospinal fluid and blood plasma in depression disorders. Chronic mild stress (CMS) and forced swimming, which can be used as animal model for depression, significantly decline GABA in central nervous system, while administration of GABA effectively ameliorates depression-like behaviors. However, other researches showed that GABA unchanged, even rose in hippocampus in depression animals, which was probably to do with discrepancies of stress factors, duration and intensity in the course of depression modeling. There are two types of GABA receptors, that is, ion receptors and metabolism receptors. The ion receptor consists of GABAAR, GABABR, and GABACR. There into, GABAAR and GABABR extensively distribute in hippocampus, and have close connection with depression. Many clinical studies manifested GABAAR dysfunction was linked to depression and anxiety disorders. Activating GABAAR apparently resist depression and anxiety disorders. But, different statements are about GABABR in depression. Recent studies showed that it was not GABABR inhibitor but GABABR agonist that had potential to antidepression.Glutamic acid (Glu) is the most important excitatory neurotransmitter in mammal central nervous system, having an exciting action on almost all the neurons in brain. Most of hippocampal neurons are Glu-ergic, no matter afferent neurons, internuncial neurons and efferent neurons. Glu contributes importantly to neuron-plasticity, emotional behavior and learning-memory. References showed that metabolic level of Glu was different in depression, but antidepressant normalized this phenomenon. Also, researches on pattern animal displayed that chronic stress increased Glu in hippocampus, and high level of Glu excessively activated NMDA receptor and induced excitatory neurotoxicity, thus causing damage to neurons. However, antagonist to NMDA receptor, including its analogue, has antidepressant functions.More and more studies declared that it was an important way of make a balance between excitatory neuro-system and inhibitory neuro-system in brain to avoid disease. Therefore, GABA and Glu become the key point in researching brain function. Appropriate stress does not lead to psych-emotion disorders, since it does not disrupt the balance between the excitatory system and the inhibitory system, which mainly arise from Glu and GABA.In order to prove of Glu, GABA and their receptors in the CUMS-induced depression, especially the mechanism of the regulation and balance between the two systems, we used the CUMS (chronic unpredictable mild stress, CUMS), intra-hippocampal microinjection of agonists and antagonist of Glu receptor and GABA receptor, and HPLC to investigate the variation of Glu and GABA, and the pathogenesis of the involved Glu and GABA receptors.Results are in the following:1. CUMS resulted in depression-like behaviors, significantly increased Glu (P<0.05) and decreased GABA (P<0.01) in hippocampus.2. MK-801, NMDAR antagonist, relieved CUMS-induced depression-like behaviors, up-regulated GABA and down-regulated Glu in hippocampus.3.Muscimol, GABAAR agonist, ameliorated CUMS-induced depression-like behaviors, decreased Glu and increased GABA in hippocampus. Balofen, GABABR agonist, induced depression-like behaviors, and reduced hippocampal Glu slightly and GABA distinctly. GP35348, GABABR antagonist, effectively ameliorated CUMS-induced depression-like behaviors, declined hippocampal Glu and raised hippocampal GABA.Analysis from the above results show disequilibrium between hippocampal Glu and GABA, that is, Glu increase and GABA decrease, is one of pathological mechanisms involved in CUMS-induced depression. The antidepression function of NMDAR antagonist MK-801 is via two ways:preventing damages to neurons from NMDAR excessive activation, and regulating presynaptic release of Glu and GABA to maintain the equilibrium. The activation of GABAAR induces antidepression, while the activation of GABABR produces despression-like behaviors, which are also achieved by balancing Glu and GABA.