| Depression is a common mental illness, with depression as the main feature. Almost every five adults have a depressive disorder, so it is called the common cold of psychiatry. With the accelerated pace of modern life, living and working pressure increases, the incidence of depression is increasing year by year. Patients with depression have suicidal tendencies. It induce social stability and economic development unfavorable. So depressive disorder are paid by more and more people. Depression is considered as the greatest threat to the population besides the heart diseases。It was regarded as one of three kinds of major diseases in the 21st century by the World Health Organization. Pathogenesis of depression is complicated, the cause remains unclearly. So far, many research data show that the morbidity of depression closely related to the reduction in brain 5-HT. 5-HT reuptake inhibitors is utilized in clinical experiment, which increase the level of central 5-HT and antidepressant effect can be achieved. There are a lot of hypotheses about neural and biochemical aspects of depression, but for decades it is ruled basically by a monoamine neurotransmitter hypothesis. Other point of the study is relatively small. Recent studies have shown that many other biochemical substances in the brain (and)or system were also involved in the etiology of depression and pathological processes. The occurrence of depression not only is related with the NE, 5-HT level, but also may be related to a variety of neurotransmitter systems and receptor dysfunction such as dopamine (DA), acetylcholine (Ach), neuropeptide (neuropeptide),γ-amino butyric acid (GABA) et al. At the same time, the occurrence of depression also may be related to neurological defects in cognitive function and nerve changes in electrophysiology. In recent years, brain-gut peptide (neuropeptide) was thinked as important in the pathogenesis of depression. The popular hypothesis is that substance P and other neurokinin mediated depression, anxiety disorder, or schizophrenia, mood disorder. So Substance P receptor antagonist (SPA) as a new type of antidepressant drug is applied by more and more people but its mechanism is not fully understood.Substance P was the first neuropeptide to be discovered and was widely distributed in the central and peripheral tissues. Studies have showed that substance P closely contact with serotonin and norepinephrine systems in the anatomy and function and involved in the cause of the depression. SP can cause a normal person produce a similar mood, sleep and neuroendocrine changes to depression patients. Plasma circulating levels of substance P increased in severe depression patients and antidepressant treatment may cause the contents near the normal level.We found that a variety of antidepressant treatment can decrease P substance in brain regions during animal experiments. SP can be seen as the important material which is linked with the occurrence of depression. The habenular nucleus (Hb), especially, lateral habenula (LHb) is the major relay station between forebrain and midbrain raphe. The study found that the rate of glucose metabolism increased in depression rat lateral habenular nucleus. Cerebral blood flow increased significantly in Hb of the depression patient. Therefore, Sartorius A et al proposed the hypothesis that the overexcitatioin of Hb activity maybe led to reduction of 5-HT and NE neurotransmitter release and increase of HPA axis activity, which led to depression. If the activities of Hb was suppressed, it will increase the release of neurotransmitters such as 5-HT and NE and achieve the purpose of anti-depressant. During controlling the behavior of animals, the LHb play an important role by affecting the dopamine and 5 - hydroxytryptamine system. 5 - HT neurons concentrated in the raphe nucleus. There are direct fiber connection between the lateral habenular nucleus and the DRN. Habenular is an important relay station, which collect limbic forebrain projection to the DRN. Habenular inhibit raphe nucleus, electrical stimulation of the lateral habenular nucleus can cause the discharge reduction in the dorsal raphe nucleus. Hb contains a variety of neurotransmitters and their receptors, such as: NE, ACh, 5-HT, GABA, DA and other classical neurotransmitters e.g. the SP, angiotensinⅡ, endogenous opioid peptides and neuropeptide Y (NPY) et.al. So SP receptor antagonist antidepressant effect may be associated with Hb. The mechanism may be the regulation of Hb on the DRN activity. Anatomical studies have shown that SP and 5-HT existed co-expression in 50% of the human brain neurons and SP can affect 5-HT neuron function. Therefore, SP receptor antagonist (SPA) are thinked to have the same antidepressant effect as 5-HT reuptake inhibitors as clinical antidepressant drugs. That antidepressant effect may be achieved by increasing the level of 5-HT in the DRN.A variety of neurotransmitters in the central nervous system formed a complex space network system. The interrelationship between SP and the mono-amine neuro- transmitters, as well as other neurotransmitters, is a worthy field of study in the central nervous system. In addition, there is no definitive conclusions about substance P content in the brain of depression patients at present. The cerebrospinal fluid studies are still lacking. NK1 receptor antagonistic agents as a new prospect of antidepressant drugs is encouraging, but it still needs more in-depth study.Therefore, we applied electrophysiology, microdialysis, HPLC, molecular biology and immunohistochemical method to prove that the role of Hb in the pathogenesis of depression. Hb is an important hub of antidepressant target for the SPA and it mediate antidepressant effect of SPA.The results showed that:(1)Whether in chronic mild stress-induced depression rats or in clomipramine -induced endogenous depression rats, there were decreased activity, loss of appetite, indifferent with experimental operation, non-resistance, the weight of rats in model group was reduced than that in control group(P<0.01);the sugar intake of rats in model group was fewer than that in control group(P<0.01). During forced swimming test the immobility time of model group was longer than that of control group(P<0.001) and the climbing time in model group was shorter than that in control group (P<0.001);Open field experimental showed that the crossing time and the rearing time in model group reduced compared with that in control group(P<0.01).(2)The result of ELISA showed that SP level of Hb in model group increased compared with that in control group (P <0.05). While SP content in rat hippocampus in two kinds of models increased slightly, but no statistically significant difference(P>0.05).(3) RT-PCR showed that NK1 receptor expression in Hb in normal control group, CLI group and CMS rats, but no NK2 and NK3 receptor expression. NK1 receptor expression had no significant difference in habenular nucleus of each group rats(P>0.05).(4)The result of western blot showed tha there were SP receptor protein in each group rats'habenular nucleus, but the contents had no differerce in each group rats. (5)The histological morphology of rats Hb by H&E staining showed that in two model groups there were habenular nucleus cell swelling, cytoplasm blank, and some hanging the central nucleus or pushed in the side. It called vacuolar degeneration changes. SP receptor-positive cells by immunohistochemistry can be found in each group LHb. However, there was no significant difference between the model group and the control group(P >0.05).(6)Microinjection of SP into lateral cerebral ventricle can increase the firing rate of neurons in LHb (P<0.01). Microinjection of SPA into lateral cerebral ventricle can decrease the firing rate of neurons in LHb (P<0.01).(7)The microdialysis analysis showed that content of glutamate increased in LHb of model rats (P<0.01). The extracellular Glu level in LHb increased after we injected SP into LHb (P <0.05). The extracellular Glu level in LHb decreased after we injected SPA into LHb (P <0.05).According to these results, we can draw the following conclusions:1.From a number of behavioral experiments, we proved the validity and reliability of chronic mild stress-induced rat depression model and clomipramine- induced rat endogenous depression model and proved that this two kinds of animals model are ideal models to study the mechanism of the pathogenesis and treatment of depression once again. As for the chronic mild stress-induced rat depression model, We can effectively increase the mode rate by increasing the type of stimulation everyday and extensing stimulation cycle.2. Two kinds of depression model rats Hb showed that cell swelling, vacuolar degeneration, SP content increased. These demonsteated that changes in form and function of Hb involved in the formation of depression. The increased SP content in Hb may be one of the reasons leading to depression.3. Administration SPA in central nervous system can reduce glutamate (Glu) levels in LHb, and inhibit the electrical activity of LHb neurons. Administration SP in central nervous system can increase glutamate levels in LHb and increase the electrical activity of LHb neurons. These proved that SPA and SP could affect the secretion of DR 5-HT by changing the function of Hb. Then SPA achieve its anti-depressant effect and SP can induce depression. Especially LHb exist the SP receptor which proved that habenular nucleus can be a target site for SP and SPA administration in central nervous system. Innovation points in this paper:1. In this study, we apply a variety of experimental methods and techniques to prove that the form and function of changes in Hb involved in the formation of depression. We detected SP changes in the depression model rats Hb. So we concluded that the elevated SP content in Hb may be an important reasons involved in the formation of depression.2. From different levels, we proved that the current clinical new antidepressants SPA affect LHb functional activity by binding with the NK1 receptor. Thus we thinked LHb as a target site for SP and SPA administration. The change of glutamate may be one of mechanisms that SPA improving depressive behavior.
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