CAJ | 학술논문

为探讨海马N-甲基-D-天冬氨酸（N-methyl-D-asparticacid,NMDA）受体与P物质（SubstanceP,SP）及其神经激肽1（neuro kinin1,NK1）受体在慢性不可预见性温和应激（chronic unpredictable mild stress,CUMS）中的作用及其关系,通过建立CUMS动物模型,大鼠海马微量注射给药,测量大鼠体重,并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测,运用高效液相色谱（HPLC）法分析大鼠海马组织中SP和谷氨酸（glutamate,Glu）的含量变化。结果显示,CUMS诱发大鼠表现出明显的抑郁样行为,海马组织中SP和Glu水平显著增加;海马注射NMDA,大鼠表现出与CUMS/SAL组相似的抑郁样行为,且海马组织中SP的含量比正常对照组显著增加;微量注射NK1受体阻断剂CP-96345和/或NMDA受体阻断剂MK-801后,大鼠抑郁样行为明显改善,且MK-801使CUMS导致的大鼠海马P物质水平升高得到明显控制,而CP-96345没有明显改变CUMS引起的海马Glu水平升高;CP-96345使NMDA引起的抑郁样行为得到极显著改善。以上结果表明,慢性应激引起大鼠海马Glu过量释放,通过激活NMDA受体,促进P物质合成释放增加,激活NK1受体,是导致抑郁样行为发生的重要途径之一。
위탐토해마N-갑기-D-천동안산（N-methyl-D-asparticacid,NMDA）수체여P물질（SubstanceP,SP）급기신경격태1（neuro kinin1,NK1）수체재만성불가예견성온화응격（chronic unpredictable mild stress,CUMS）중적작용급기관계,통과건립CUMS동물모형,대서해마미량주사급약,측량대서체중,병채용당수편애측시、광장실험화현미실험등방법대대서진행행위학검측,운용고효액상색보（HPLC）법분석대서해마조직중SP화곡안산（glutamate,Glu）적함량변화。결과현시,CUMS유발대서표현출명현적억욱양행위,해마조직중SP화Glu수평현저증가;해마주사NMDA,대서표현출여CUMS/SAL조상사적억욱양행위,차해마조직중SP적함량비정상대조조현저증가;미량주사NK1수체조단제CP-96345화/혹NMDA수체조단제MK-801후,대서억욱양행위명현개선,차MK-801사CUMS도치적대서해마P물질수평승고득도명현공제,이CP-96345몰유명현개변CUMS인기적해마Glu수평승고;CP-96345사NMDA인기적억욱양행위득도겁현저개선。이상결과표명,만성응격인기대서해마Glu과량석방,통과격활NMDA수체,촉진P물질합성석방증가,격활NK1수체,시도치억욱양행위발생적중요도경지일。
Stressors markedly influence central neurochemical and hormonal processes and thus play a pivotal role in the occurrence of depressive illnesses.As the center for stress response and the potential target for stressful provocation,hippocampus is becoming a focus in depression research.Although a large number of behavioral paradigms have been proposed as animal models of depression,only a few are considered as potentially useful research tools with sufficient validity.The most accepted one is chronic unpredictable mild stress rodent model,in which rats were subjected chronically and unpredictably to a variety of stressors including immersion in cold water,tail pinch,day and night reversed and so on.There are several theoretic mechanisms for depression,such as monoamine neurotransmitter imbalance theory,neural plasticity theory,but none of them can fully elucidate the formation of depression.Due to weakness of the antidepressant-like effect of monoamines,glutamate（Glu） and its receptors,especially N-methyl-D-aspartic acid（NMDA） receptor,and neuropeptides such as neuropeptide Y（NPY）,substance P（SP）,are drawing closer attention in recent years.Here,we are attempted to explore the interaction between Glu/NMDA receptor and SP/neurokinin 1（NK1） receptor in chronic unpredictable mild stress（CUMS）-induced depression.CUMS-induced depression model was established in 250~300g weighted 90-day old Sprague-Dawley rats.Intrahippocampal microinjection of NK1 receptor antagonist CP-96345,NMDA receptor agonist NMDA or NMDA receptor antagonist MK-801 was performed under stereotaxic guide cannula.The body weight of rats was weighed on the 1st,7th,14th,and 21st days during the experiment.The behavioral conducts were observed by means of sucrose consumption test,open field test and tail suspension test.The substance P（SP） and glutamate（Glu） content in hippocampus were separately determined by High performance liquid chromatography（HPLC）.One-way ANOVA,LSD and repeated measures in SPSS were used in datum analysis.Our data suggest that CUMS significantly induced the depressive-like behaviors in animals and the content of SP and Glu in hippocampus had increased significantly.Microinjection of NMDA into hippocampus resulted in similar animal depressive-like behaviors and an increased SP content compared to the CON/SAL group.Intrahippocampal injections of CP-96345 or MK-801 had effectively improved the depression-like behaviors induced by CUMS,and the elevation of SP level in hippocampus was attenuated in MK-801 injection,whereas Glu level remained unchanged in CP-96345 injection.Our results imply that hippocampal NMDA receptor may contribute to chronic stress induced depressive-like behaviors via SP-NK1 receptor pathway,of which,chronic stresses can induce excessive release of Glu which consequently increases the synthesis and release of SP through over-activation of NMDA receptor,ultimately,over-released SP aberrantly activates its NK1 receptor.