The Role Of α7AchRs In Hippocampus Of Chronic Stress - Induced Depression

Depression is a type of mental disorder that have adverse and diverse roles in affecting a people’s physical and mental health, accompanied by a high incidence and suicide rate. So the etiology, pathogenesis and prevention strategies of depression have attracted widespread concern. Plenty of evidences proved that the depression is related to chronic stress. Establishing the model of chronic unpredictable mild stress (CUMS)-induced depression model is one of the most important analytic methods for depression, which can be used to filter(screen) antidepressant drug, has played an important role in uncovering the mechanism of antidepressant and guiding pathophysiological studies of depression. Studies also showed that the hippocampus, an important part of the limbic system, is crucial for regulating stress responses. Moreover,5-hydroxytryptamine (5-HT), glutamic acid (Glu), other neurotransmitters and their receptors in the hippocampus are closely related to the occurrence of depression.a7nAChRs is one kind of homologous pentameric subtypes of N-AChR. They are spread over in the hippocampus, cerebral cortex, hypothalamus and several brainstem nuclei. Studies suggested that the presence of acetylcholinesterase in the hippocampus is related to the occurrence of depression. Nicotinic acetylcholine receptors (nAChRs) have been studied as potential targets for drug treatment of mental illness, but researches always used to focusing on the mechanism and therapy of cognitive disorders. Current scientific data and clinical experiments proved that the occurrence of depression is related to nAChRs. Studies indicated that5-serotonergic neurons contain a7nAChRs subtypes. Nicotine increased5-HT release frequency in dorsal raphe through the activation of a7nAChRs, meanwhile, it also increase the concentration of5-HT in some prefrontal regions. There are strong evidences showing that a7nAChRs owe high permeability to Ca2+mainly located in the terminal of glutamatergic neurons which could maintain or promote the release of Glu, similar to the modulation of Ach stimulate Glu release in the cerebellum of rat is mediated by the activation of presynaptic a7nAChRs. Experiments also proved that the activation of these receptors in the hippocampus could raise the concentration of Glu. Mecamylamine and a-bungarotoxin, selective antagonists of a7nAChRs, have the ability to prevent the neurotoxicity of glutamate.It is said that mechanism of synaptic changes may also be due to the activation of a7nAChRs. However it is still unclear whether the α7nAChRs in hippocampus play an important role in chronic unpredictable stress depression and whether the role works via regulating the release of5-HT and Glu. In order to solve this problem, we established a chronic unpredictable mild stress model microinjecting a7nAChRs agonists (SSR180711) and antagonists (MLA) in bilateral hippocampal of experimental animal. The behavior of rats was observed by means of their body weight changes, sucrose consumption test, open field test and tail suspension test. The concentration of5-HT and Glu were detected by HPLC.and the expression of NMDA receptors’subunits in hippocampus (NR1and NR2B subunits), and a7AChRs were detected by Western blot. The level of phosphorylation of a7AChRs receptor was separately detected by ELISA. The results were as follows:Our data suggest that CUMS group, compared to control group, significantly induced the depressive-like behaviors in rats, and increased the concentration of Glu(n=6, p<0.01), the expression(n=6, p<0.05)and the level of phosphorylation of α7AChRs (P-a7AChRs)(n=6, p<0.01)in hippocampus, while the expression of NMDA receptors’subunits NR1(n=6, p<0.05)/NR2B (n=6, p<0.01) were decreased significantly. Microinjected α7AChRs agonists (SSR180711) and antagonists (MLA) into hippocampus effectively improved the depression-like behaviors, which was induced by CUMS. The concentration of Glu was decreased(p <0.01),while the expression of NR1(p<0.05)/NR2B(p<0.01)were increased by MLA significantly, and MLA had no effect on5-HT concentration. On the contrary, SSR180711could increase5-HT concentration remarkably(p<0.01), but it had no effect on the concentration of Glu and the expression of NMDA receptors’ subunits NR1/NR2B. Injecteda7nAChRs agonist MLA or antagonist SSR180711in normal rat hippocampal had no effect on the performance of the animal’s behavior. Compared to CON/SAL group,5-HT concentration in SSR180711/SAL group significantly increased(p<0.01), and the concentration of Glu increased too(p<0.05), but the expression of NR1/NR2B decreased(p<0.05),while injected antagonists MLA in normal rat hippocampal had no significant effect on normal rat the concentration of Glu and the expression of NR1/NR2B of (0.08>p>0.05).These results suggested that CUMS may contribute to the activation of a7nAChRsandthe exaltation of p-a7nAChRs, and these may lead to excessive release of Glu and reduction of the expression of NR1/NR2B. a7nAChRs agonists S SR180711and antagonists MLA could significantly improve depression-like behavior caused by CUMS, but their antidepressant mechanisms were different. MLA resulted in the reduction of Glu level and the elevation of the expression of NR1/NR2B, which reversed the depressive-like behaviors in the end. But SSR180711could significantly elevate the level of5-HT. In a word, stress lead to depression-like behavior that may be induced by the activation of a7nAChRs or the exaltation of p-a7nAChRs. a7nAChRs agonists, and antagonists may act on5-serotonergic and glutamatergic system respectively, and finally lead to the release of5-HT and Glu. It is likely to be the antidepressant mechanism of antagonist and agonist.