Tau和MAP-2在CCK-8减轻吗啡致空间记忆损害中的作用及机制研究
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摘要
阿片类物质的长期应用可以导致药物耐受和成瘾。阿片成瘾者在形成对药物依赖的病理性记忆的同时还伴有正常的认知和学习记忆的损害。空间记忆是一类关于场景和事件的记忆，急慢性吗啡作用均可导致空间学习和记忆的损害。八肽胆囊收缩素（Cholecystokinin octopeptide, CCK-8）作为一种目前最强的抗阿片肽类物质以多种形式广泛存在于中枢和周围神经系统，在食物性记忆模型，回避反应以及空间识别中发挥了重要的调节作用。然而，CCK-8对吗啡致记忆损害作用及其相关机制尚未见报道。
已知突触可塑性是学习和记忆的生理基础，而海马的突触可塑性改变与空间记忆密切相关。神经细胞骨架系统在神经元突触可塑性调节中发挥着重要的作用。Tau和MAP-2作为微管相关蛋白分别定位于轴突和树突，它们通过影响微管的稳定性参与了突触前、突触后可塑性以及神经元稳态可塑性的调节。以往研究结果提示tau和MAP-2的表达及磷酸化状态与学习和记忆密切相关。但是，tau和MAP-2是否参与了CCK-8对吗啡致突触可塑性改变的影响尚不明确。
因此，本实验观察了外源性CCK-8对慢性及急性吗啡作用小鼠空间记忆的影响，然后，进一步在整体和细胞水平探讨了tau和MAP-2在CCK-8调节吗啡致突触可塑性改变中的作用，以明确CCK-8改善吗啡致空间记忆损害的作用机制。
第一部分：CCK-8对吗啡作用小鼠空间记忆的影响
目的：应用Morris水迷宫分别观察吗啡依赖和急性吗啡作用对小鼠空间参考记忆的影响；在吗啡作用小鼠侧脑室给予不同剂量的CCK-8，以评价外源性CCK-8对吗啡致空间记忆损害的作用，同时观测了CCK-8单独作用对空间参考记忆的作用。
方法：①按照剂量递增的方式建立小鼠吗啡依赖模型（第1-6天皮下注射吗啡剂量分别为20，40，60，80，100，100mg/kg，每天2次，间隔12小时），或者侧脑室注射不同剂量（0.001，0.01，0.1和1μg）的CCK-8每天2次，间隔12小时，在接下来的7天进行Morris水迷宫的适应、训练和测试，训练和测试均在药物注射后30分钟进行。在此期间小鼠继续每天2次进行皮下注射100mg/kg吗啡或者侧脑室注射CCK-8，以观测慢性吗啡和外源CCK-8单独作用对小鼠空间参考记忆的影响；在每次皮下注射吗啡前30分钟予侧脑室给予不同剂量（0.001，0.01，0.1和1μg）的CCK-8以观测外源性CCK-8对慢性吗啡致空间参考记忆损害的作用。②应用2天Morris水迷宫模型，分别在第一天训练前以及第二天测试前30分钟腹腔注射1，5，10mg/kg的吗啡或者侧脑室注射CCK-8（0.001，0.01，0.1和1μg）以观测急性吗啡和外源性CCK-8单独作用对空间参考记忆获得和再现的影响；分别在吗啡前或者吗啡后给予不同剂量的CCK-8（0.001，0.01，0.1和1μg）以观测外源性CCK-8对急性吗啡损害空间参考记忆获得的作用。
结果：①本部分实验共使用552小鼠用于最终的统计学分析。
②慢性吗啡处理明显降低了小鼠在空间探索实验中的成绩，但是并不影响小鼠在定向航行实验中的表现，并且慢性吗啡作用对空间记忆的损害可以延迟至吗啡自发戒断后7天；相对于生理盐水对照组，单独给予CCK-8（0.1和1μg）组小鼠在定向航行实验和空间探索实验的成绩均有明显的提高；CCK-8（0.01，0.1和1μg）+吗啡组在定向航行实验和空间探索实验的成绩较吗啡组明显提高。
③训练前腹腔注射吗啡（5和10mg/kg）明显损害小鼠在定向航行实验和空间探索实验的表现，但是测试前腹腔注射吗啡（1，5和10mg/kg）对小鼠在水迷宫中的表现无明显影响；训练前侧脑室注射CCK-8（0.01，0.1和1μg）以及测试前注射CCK-8（0.1和1μg）均可提高小鼠在定向航行实验和空间探索实验中的成绩；训练前和测试前给予CCK-8（0.1和1μg）均可明显减轻吗啡（10mg/kg）对小鼠空间参考记忆获得的影响，但是CCK-8（0.001和0.01μg）却无明显的作用。
小结：①慢性吗啡作用明显损害了小鼠的空间参考记忆，并且这种损害作用可以延迟至吗啡停药后7天；侧脑室预给予CCK-8可改善慢性吗啡诱导的空间参考记忆损害，并且CCK-8单独作用也可明显促进小鼠的空间参考记忆；②急性吗啡作用明显影响了小鼠空间参考记忆的获得，但不损害空间参考记忆的再现；训练前和测试前给予CCK-8均可明显改善吗啡致空间参考记忆获得的损害；训练前或测试前单独给予CCK-8可分别促进小鼠空间参考记忆的获得和再现，且呈剂量依赖性。
第二部分：CCK-8减轻吗啡致空间记忆损害的机制研究1CCK-8对吗啡作用小鼠海马乙酰胆碱含量以及树突棘密度的影响
目的：通过观测外源性CCK-8对急慢性吗啡作用小鼠海马乙酰胆碱含量以及树突棘密度的影响，明确CCK-8减轻吗啡致空间记忆损害的突触可塑性机制。
方法：建立急慢性吗啡作用动物模型，应用液质联用技术及高尔基染色观察乙酰胆碱的含量以及树突棘密度。
结果：本部分实验共有48只小鼠用于统计学分析。CCK-8（1μg）预处理可明显翻转急性吗啡作用后海马乙酰胆碱含量的降低；CCK-8（1μg）急性作用可使海马乙酰胆碱递质含量明显升高；慢性吗啡或CCK-8单独作用均可明显增加海马乙酰胆碱的含量，但CCK-8（1μg）预处理并不影响吗啡作用。CCK-8（1μg）预处理可明显抑制慢性吗啡作用后海马CA1区的树突棘密度的降低；慢性CCK-8单独作用可明显升高海马CA1区的树突棘密度。2CCK-8对吗啡作用小鼠海马tau和MAP-2表达的影响
目的：通过观测海马微管相关蛋白tau和MAP-2表达的改变，探讨骨架蛋白系统在CCK-8对吗啡致突触可塑性改变中的作用。
方法：应用RT-PCR以及Western Blot检测海马组织tau和MAP-2的mRNA及蛋白表达。
结果：本部分实验共有48只小鼠用于统计学分析。急性吗啡或CCK-8单独作用均不影响海马tau和MAP-2的表达， CCK-8（1μg）预处理可明显抑制急性吗啡作用后tau Ser396以及MAP-2Ser136、Thr1620/1623位点磷酸化的增加；而tau Ser262位点的磷酸化水平在急性吗啡作用后无明显变化，在CCK-8急性作用后明显增高。
CCK-8（1μg）预处理可明显翻转慢性吗啡作用后海马tau和MAP-2表达的降低，而慢性CCK-8单独作用仅可上调MAP-2的表达，对tau的表达无明显作用；CCK-8（1μg）预处理明显抑制了慢性吗啡诱导tauSer262和Ser396以及MAP-2Ser136和Thr1620/1623位点磷酸化水平的上调；CCK-8（1μg）慢性作用也可抑制tau和MAP-2在各位点的磷酸化。3CCK-8对吗啡诱导tau和MAP-2磷酸化改变的机制研究
目的：在建立吗啡急、慢性作用细胞模型的基础上，观察外源性CCK-8对吗啡诱导tau和MAP-2磷酸化相关激酶以及磷酸化酶的作用，初步探讨CCK-8影响吗啡诱导tau和MAP-2磷酸化的具体机制。
方法：建立吗啡急性和慢性作用细胞模型，应用Western Blot以及酶活性试剂盒检测tau和MAP-2磷酸化以及PKA，GSK-3β以及PP2A的活性。
结果：SH-SY5Y细胞的cAMP水平在吗啡作用3小时以内降低，而在24小时以后明显上调；100M吗啡作用48小时后，应用10M纳洛酮进行催促戒断后cAMP水平明显上调。因此，分别以100M吗啡作用SH-SY5Y细胞30分钟以及48小时作为急慢性吗啡细胞模型。
与动物实验结果一致，CCK-8可明显抑制急慢性吗啡作用后tau和MAP-2磷酸化水平的上调；为了明确tau和MAP-2磷酸化的机制，进一步观察了PKA，GSK-3β以及PP2A活性的变化，结果发现上述三种酶活性在急性吗啡作用后明显下调，而在慢性吗啡作用后均明显上调；PKA的特异抑制剂H-89可明显降低慢性吗啡诱导tau Ser262磷酸化水平的升高，而应用GSK-3β特异抑制剂SB216763后tau的Ser396位点以及MAP-2的Ser136和Thr1620/1623位点的磷酸化水平均明显下降。
10-6M CCK-8干预可明显翻转急性吗啡作用引起的PP2A活性的下降，急性CCK-8单独作用明显抑制PKA和GSK-3β的活性，但是对PP2A活性并无明显影响；CCK-8可明显抑制慢性吗啡引起的PKA和GSK-3β活性的增高，同时慢性单独作用也可明显降低PKA和GSK-3β的活性。
小结：外源性CCK-8可通过增加海马乙酰胆碱含量以及树突棘密度减轻吗啡致空间记忆的损害；CCK-8可通过下调tau和MAP-2的磷酸化水平调节吗啡诱导的突触可塑性变化。
结论：本文系统研究了外源性CCK-8对急慢性吗啡致空间记忆损害的影响以及突触可塑性机制，在整体和细胞水平观察了CCK-8对急慢性吗啡处理后tau和MAP-2表达及磷酸化改变的影响，并探讨了tau和MAP-2磷酸化的相关酶活性机制。得出以下结论：
1侧脑室给予CCK-8（0.01、0.1、1μg）可明显减轻吗啡依赖小鼠空间参考记忆的损害；训练前和测试前给予CCK-8（0.1、1μg）均可明显减轻急性吗啡诱导的空间参考记忆获得的损害。提示大剂量外源性CCK-8可通过自身对学习和记忆的影响和/或对阿片肽的拮抗作用参与了其减轻吗啡诱导空间记忆损害的过程。
2CCK-8（1μg）可通过增加海马乙酰胆碱含量以及树突棘密度减轻吗啡致空间记忆的损害，且通过下调tau和MAP-2的磷酸化水平调节吗啡诱导的突触可塑性变化。
3急性吗啡作用主要通过抑制PP2A活性上调tau和MAP-2磷酸化水平，而慢性吗啡作用则通过增强PKA和GSK-3β活性诱导了tau和MAP-2的磷酸化；急慢性CCK-8单独作用主要通过抑制PKA和/或GSK-3β活性使tau和MAP-2磷酸化水平下降；CCK-8干预可通过上调急性吗啡作用引起的PP2A活性下降及下调慢性吗啡引起的PKA和GSK-3β活性增高，抑制了吗啡诱导tau和MAP-2磷酸化水平的增高。
Long-term application of opioids can lead to tolerance and adiiction.Meanwhile, cognitive and learning and memory was impaired by opioidstreatment. Spatial learning and memory is a kind of scenes and events memory,and morphine dependence or acute morphine treatment could induce spatialmemory impairment. Cholecystokinin octopeptide (CCK-8), one of the mostefficient anti-opioid peptides, is widely spread in the central and peripheralnervous system, which play an important role in modulating memory processsuch as avoidance reaction, spatial identification and so on. However, theeffect of CCK-8on morphine induced memory impairment and its relatedmechanism is unclear.
Synaptic plasticity is the physiological basis of learning and memory, andspatial learning and memory impairment is closely related to the synapticplasticity change in hippocampus region. The skeletal system plays animportant role in regulating synaptic plasticity. Tau and MAP-2regulates thepre-synaptic and postsynaptic plasticity and steady-state plasticity of neuronsby affecting the stability of microtubules which are located in the axon anddendrites respectively. Study showed that phosphorylation state of tau andMAP-2was also participated in the learning and memory process. But,whether tau and MAP-2were responsible for the effect of CCK8on morphineinduced synaptic plasticity change is not clear.
We use Morris water maze to observe the effect of exogenous CCK8onspatial reference memory impairment in acute and chronic morphine-treatedmice. Then we aimed to clarify the role of skeleton associated protein ineffects of CCK-8on synaptic plasticity change induced by morphine toexplore the mechanism of CCK-8on memory impairment by morphine.
Part1: Effects of CCK-8on spatial memory in morphine-treated mice
Objective: We use Morris water maze to observe the effect of morphinedependence and acute morphine on spatial reference memory; different dosesof exogenous CCK-8were given before morphine to evaluate effect of CCK-8on spatial memory in morphine-treated mice; effect of exogenous CCK-8treatment alone on spatial reference memory was also observed.
Methods:①Morphine dependent model was established by increasingdoses manner (1-6days, morphine was subcutaneous injected at dose followed:20,40,60,80,100,100mg/kg, respectively,2times a day,12hours interval);different doses (0.001,0.01,0.1and1ug) of CCK-8was given by lateralventricle injection,2times a day at12hours interval. Morris water maze inthe next7days to adapt, training and testing, training and tests are conducted30minutes after drug injection. During this period, morphine100mg/kg orCCK-8were still given to mice; to observe effect of exogenous CCK-8onspatial reference memory in chronic morphine-treated mice, CCK-8was given30minutes before every morphine injection.②we adopted a2-day Morriswater maze model to assess acute drug treatment on spatial memory.1,5andor CCK-8(0.001,0.01,0.1and1μg, i.c.v)30minutes before training and testto assess effect of morphine or CCK-8on spatial reference memoryacquisition and retrieval respectively;10mg/kg morphine(i.p) was given30minutes before training, and different doses of CCK-8(0.001,0.01,0.001and1μg) were given30minutes before morphine or test to observe exogenousCCK-8on acute morphine induced spatial memory acquisition impairment.
Results:①552mice were included in the final statistical analyses.
②Chronic morphine significantly impaired spatial reference memory onthe probe test but did not affect the performance in place navigation trails;Spatial reference memory impairment by chronic morphine could delay to7days after morphine spontaneous withdrawal; CCK-8(0.1and1μg) alonesignificantly improved the spatial reference memory; CCK8(0.01,0.1and1μg) significantly improved the impairment of spatial reference memoryinduced by chronic morphine.
③Morphine (5and10mg/kg) treatment30minutes before training significantly impaired spatial reference memory acquisition in mice, whichshowed a poor performance in place navigation trails and probe test in watermaze experiment, but morphine (1,5, and10mg/kg) treatment30minutesbefore test had no effect on memory retrieval; CCK-8(0.01,0.01and1μg)treatment30minutes before training or CCK-8(0.1and1μg) before test couldpromote the acquisition and retrieval of spatial reference memory respectively;CCK-8(0.1and1μg) before training or test could significantly improveimpairment of spatial memory acquisition by morphine (10mg/kg) in mice,but CCK-8(0.001and0.01μg) had no obvious effect.
Summary:①This part of study found that chronic morphine obviouslyimpaired spatial reference memory, and the damage can be delay to7daysafter morphine withdrawal; CCK-8(0.01,0.1,1μg) could improve the spatialreference memory damage induced by chronic morphine; at the same time,CCK-8(0.1and1μg) alone could significantly improved the spatial referencememory in mice.
②Acute morphine significantly affected the spatial reference memoryacquisition in mice, but did not affect memory retrieval; CCK-8before thetraining or test significantly improved impairment of memory acquisitioninduced by morphine; CCK-8treatment alone could improved spatialreference memory acquisition or retrieval.
Part2: mechanism of CCK-8alleviating spatial memory impairment bymorphine
1effect of CCK-8on acetylcholine content and dendritic spine density inhippocampus of morphine-treated mice
Objective: Acetylcholine content and dendritic spine density change inhippocampus were observed to clarify the role of synaptic plasticity change inCCK-8on spatial memory in morphine-treated mice.
Methods: We established acute or chronic morphine mice model first,then LC-MS and Golgi staining were adopted to detect acetylcholine levelsand density of dendritic spines in morphine or CCK-8treatment.
Results:48mice were included in the final statistical analyses. Acute morphine significantly decreased the content of acetylcholine in thehippocampus, but acetylcholine content increased after chronic morphinetreatment; Acute or chronic CCK-8(1μg) could significantly increaseacetylcholine content in hippocampus; pre-injection of CCK-8(1μg) couldobviously reverse acetylcholine content decreased by acute morphine, but hadno obvious effect on chronic morphine. Chronic morphine significantlyreduced density of dendritic spines in the hippocampus; Chronic CCK-8(1μg)alone obviously increased density of dendritic spines in the hippocampus;Pre-injection of CCK-8(1μg) could obviously reversed effect of hronicmorphine on density of dendritic spines in hippocampus.
2effect of CCK-8on tau and MAP-2expression in hippocampus ofmorphine-treated mice
Objective: Microtubule associated protein tau and MAP-2expression inhippocampus were observed, in order to investigate the role of skeletonprotein system in synaptic plasticity changes.
Methods: Tau and MAP-2expression in hippocampus by morphine andCCK-8treatment were detected by RT-PCR and Western Blot.
Results:48mice were included in the final statistical analyses. Acutemorphine or CCK-8treatment alone did not affect tau and MAP-2expressionin hippocampal, pre-injection of CCK-8(1μg) could obviously reverse theeffect of acute morphine induced phosphorylation of tau Ser396, MAP-2Ser136and Thr1620/1623; phosphorylation of tau Ser262had no obviouschange after acute morphine treatment, and was increased by acute CCK-8treatment.
Pre-injection of CCK-8(1μg) could obviously reverse the effect chronicmorphine on tau and MAP-2expression-downregulation and phosphorylationup-regulation in hippocampal; chronic CCK-8(1μg) treatment had no effecton the expression of tau, but obviously up-regulated the expression of MAP-2,and deceased phosphorylation level of tau and MAP-2.
3mechanism of CCK-8downregulating morphine induced tau and MAP-2phosphorylation
Objective: On the basis of acute morphine and morphine chronic cellmodel is established, we focused on activity of kinase and phosphorylaserelated to tau and MAP-2phosphorylation, in order to clarify the mechanismsof tau and MAP-2phosphorylation by morphine or CCK-8treatment.
Methods: We observed intracellular cAMP level by time distinguishfluorescence detection, in order to confirm the acute and chronic morphinecell model was success established. Western Blot and enzyme activity kitswere used to detected tau and MAP-2phosphorylation and PKA, GSK-3βandPP2A activity changes.
Results: cAMP level in SH-SY5Y cells is decreased within3h andincreased after24h of morphine treatment; cAMP level obviouslyup-regulated by10M naloxone in SH-SY5Y cell treaed with100Mmorphine for48h. SH-SY5Y treated with100M morphine for30minutes or48hours as acute or chronic morphine cell model.
Cosistant with animal experiment, pre-treatment of CCK-8obviouslydecreased phosphorylation level of tau and MAP-2induced by acute orchronic morphine; to explore the mechanism of tau and MAP-2phosphorylation, PKA, GSK-3β and PP2A activity were detected. Resultsshowed that PKA, GSK-3β and PP2A activity were significantly decreased orincreased in acute or chronic morphine treatment SH-SY5Y cell; the PKAspecific inhibitors H-89could significantly reversed tau Ser262phosphorylation by chronic morphine, and GSK-3β specific inhibitorsSB216763significantly reversed phosphorylation of tau in Ser396and MAP-2in Ser136and Thr1620/1623.
Acute CCK-8could increase activity of PKA and decrease activity ofGSK-3β respectively, PP2A activity showed no obvious change; ChronicCCK-8could obviously decreased the activity of PKA and GSK-3β butincreased PP2A activity significantly. Pre-injection with10-6M of CCK-8could obviously reverse PP2A activity by acute morphine treatment, andreverse PKA and GSK-3β activity by chronic morphine treatment.
Summary: This part of the study indicated that exogenous CCK-8couldrelieve morphine induced changes in synaptic plasticity by regulatingacetylcholine content and dendritic spines density in hippocampus; the rationof phosphorylation and dephosphorylation level of tau and MAP-2might beparticipated in effect of CCK-8on morphine induced synaptic plasticitychange.
Conclusions: This study reveals the effect of exogenous CCK-8on acuteand chronic morphine-induced spatial reference memory impairment andsynaptic plasticity mechanism, effect of CCK-8on morphine-inducedphosphorylation of tau and MAP-2and its mechanism were observed inanimal and SH-SY5Y cell. We can reach the conclusion as follows:
1CCK-8(0.01,0.1,1μg) could improve the spatial reference memorydamage induced by chronic morphine; CCK-8(0.1and1μg) before thetraining or test significantly improved impairment of memory acquisitioninduced by acute morphine. High dose of CCK-8may improve spatialmemory loss by morphine through anti-opiod way and/or the effect onmemory regulation itself.
2Exogenous CCK-8(1μg) could relieve morphine induced changes insynaptic plasticity by regulating acetylcholine content and dendritic spinesdensity in hippocampus, and phosphorylation level of tau and MAP-2might be participated in effect of on morphine induced synaptic plasticitychanges.
3Acute morphine increased phosphorylation level of tau and MAP-2bydecreasing PP2A activity, PKA and GSK-3β might be major responsiblefor tau and MAP-2phosphorylation by chronic morphine treatment;10-6Mof CCK-8might decreased tau and MAP-2phosphorylation throughinhibiting PKA and/or GSK-3β activity; pre-injection with10-6M ofCCK-8could obviously reversed PP2A activity by acute morphinetreatment, and reversed PKA and GSK-3β activity by chronic morphinetreatment.
已知突触可塑性是学习和记忆的生理基础，而海马的突触可塑性改变与空间记忆密切相关。神经细胞骨架系统在神经元突触可塑性调节中发挥着重要的作用。Tau和MAP-2作为微管相关蛋白分别定位于轴突和树突，它们通过影响微管的稳定性参与了突触前、突触后可塑性以及神经元稳态可塑性的调节。以往研究结果提示tau和MAP-2的表达及磷酸化状态与学习和记忆密切相关。但是，tau和MAP-2是否参与了CCK-8对吗啡致突触可塑性改变的影响尚不明确。
因此，本实验观察了外源性CCK-8对慢性及急性吗啡作用小鼠空间记忆的影响，然后，进一步在整体和细胞水平探讨了tau和MAP-2在CCK-8调节吗啡致突触可塑性改变中的作用，以明确CCK-8改善吗啡致空间记忆损害的作用机制。
第一部分：CCK-8对吗啡作用小鼠空间记忆的影响
目的：应用Morris水迷宫分别观察吗啡依赖和急性吗啡作用对小鼠空间参考记忆的影响；在吗啡作用小鼠侧脑室给予不同剂量的CCK-8，以评价外源性CCK-8对吗啡致空间记忆损害的作用，同时观测了CCK-8单独作用对空间参考记忆的作用。
方法：①按照剂量递增的方式建立小鼠吗啡依赖模型（第1-6天皮下注射吗啡剂量分别为20，40，60，80，100，100mg/kg，每天2次，间隔12小时），或者侧脑室注射不同剂量（0.001，0.01，0.1和1μg）的CCK-8每天2次，间隔12小时，在接下来的7天进行Morris水迷宫的适应、训练和测试，训练和测试均在药物注射后30分钟进行。在此期间小鼠继续每天2次进行皮下注射100mg/kg吗啡或者侧脑室注射CCK-8，以观测慢性吗啡和外源CCK-8单独作用对小鼠空间参考记忆的影响；在每次皮下注射吗啡前30分钟予侧脑室给予不同剂量（0.001，0.01，0.1和1μg）的CCK-8以观测外源性CCK-8对慢性吗啡致空间参考记忆损害的作用。②应用2天Morris水迷宫模型，分别在第一天训练前以及第二天测试前30分钟腹腔注射1，5，10mg/kg的吗啡或者侧脑室注射CCK-8（0.001，0.01，0.1和1μg）以观测急性吗啡和外源性CCK-8单独作用对空间参考记忆获得和再现的影响；分别在吗啡前或者吗啡后给予不同剂量的CCK-8（0.001，0.01，0.1和1μg）以观测外源性CCK-8对急性吗啡损害空间参考记忆获得的作用。
结果：①本部分实验共使用552小鼠用于最终的统计学分析。
②慢性吗啡处理明显降低了小鼠在空间探索实验中的成绩，但是并不影响小鼠在定向航行实验中的表现，并且慢性吗啡作用对空间记忆的损害可以延迟至吗啡自发戒断后7天；相对于生理盐水对照组，单独给予CCK-8（0.1和1μg）组小鼠在定向航行实验和空间探索实验的成绩均有明显的提高；CCK-8（0.01，0.1和1μg）+吗啡组在定向航行实验和空间探索实验的成绩较吗啡组明显提高。
③训练前腹腔注射吗啡（5和10mg/kg）明显损害小鼠在定向航行实验和空间探索实验的表现，但是测试前腹腔注射吗啡（1，5和10mg/kg）对小鼠在水迷宫中的表现无明显影响；训练前侧脑室注射CCK-8（0.01，0.1和1μg）以及测试前注射CCK-8（0.1和1μg）均可提高小鼠在定向航行实验和空间探索实验中的成绩；训练前和测试前给予CCK-8（0.1和1μg）均可明显减轻吗啡（10mg/kg）对小鼠空间参考记忆获得的影响，但是CCK-8（0.001和0.01μg）却无明显的作用。
小结：①慢性吗啡作用明显损害了小鼠的空间参考记忆，并且这种损害作用可以延迟至吗啡停药后7天；侧脑室预给予CCK-8可改善慢性吗啡诱导的空间参考记忆损害，并且CCK-8单独作用也可明显促进小鼠的空间参考记忆；②急性吗啡作用明显影响了小鼠空间参考记忆的获得，但不损害空间参考记忆的再现；训练前和测试前给予CCK-8均可明显改善吗啡致空间参考记忆获得的损害；训练前或测试前单独给予CCK-8可分别促进小鼠空间参考记忆的获得和再现，且呈剂量依赖性。
第二部分：CCK-8减轻吗啡致空间记忆损害的机制研究1CCK-8对吗啡作用小鼠海马乙酰胆碱含量以及树突棘密度的影响
目的：通过观测外源性CCK-8对急慢性吗啡作用小鼠海马乙酰胆碱含量以及树突棘密度的影响，明确CCK-8减轻吗啡致空间记忆损害的突触可塑性机制。
方法：建立急慢性吗啡作用动物模型，应用液质联用技术及高尔基染色观察乙酰胆碱的含量以及树突棘密度。
结果：本部分实验共有48只小鼠用于统计学分析。CCK-8（1μg）预处理可明显翻转急性吗啡作用后海马乙酰胆碱含量的降低；CCK-8（1μg）急性作用可使海马乙酰胆碱递质含量明显升高；慢性吗啡或CCK-8单独作用均可明显增加海马乙酰胆碱的含量，但CCK-8（1μg）预处理并不影响吗啡作用。CCK-8（1μg）预处理可明显抑制慢性吗啡作用后海马CA1区的树突棘密度的降低；慢性CCK-8单独作用可明显升高海马CA1区的树突棘密度。2CCK-8对吗啡作用小鼠海马tau和MAP-2表达的影响
目的：通过观测海马微管相关蛋白tau和MAP-2表达的改变，探讨骨架蛋白系统在CCK-8对吗啡致突触可塑性改变中的作用。
方法：应用RT-PCR以及Western Blot检测海马组织tau和MAP-2的mRNA及蛋白表达。
结果：本部分实验共有48只小鼠用于统计学分析。急性吗啡或CCK-8单独作用均不影响海马tau和MAP-2的表达， CCK-8（1μg）预处理可明显抑制急性吗啡作用后tau Ser396以及MAP-2Ser136、Thr1620/1623位点磷酸化的增加；而tau Ser262位点的磷酸化水平在急性吗啡作用后无明显变化，在CCK-8急性作用后明显增高。
CCK-8（1μg）预处理可明显翻转慢性吗啡作用后海马tau和MAP-2表达的降低，而慢性CCK-8单独作用仅可上调MAP-2的表达，对tau的表达无明显作用；CCK-8（1μg）预处理明显抑制了慢性吗啡诱导tauSer262和Ser396以及MAP-2Ser136和Thr1620/1623位点磷酸化水平的上调；CCK-8（1μg）慢性作用也可抑制tau和MAP-2在各位点的磷酸化。3CCK-8对吗啡诱导tau和MAP-2磷酸化改变的机制研究
目的：在建立吗啡急、慢性作用细胞模型的基础上，观察外源性CCK-8对吗啡诱导tau和MAP-2磷酸化相关激酶以及磷酸化酶的作用，初步探讨CCK-8影响吗啡诱导tau和MAP-2磷酸化的具体机制。
方法：建立吗啡急性和慢性作用细胞模型，应用Western Blot以及酶活性试剂盒检测tau和MAP-2磷酸化以及PKA，GSK-3β以及PP2A的活性。
结果：SH-SY5Y细胞的cAMP水平在吗啡作用3小时以内降低，而在24小时以后明显上调；100M吗啡作用48小时后，应用10M纳洛酮进行催促戒断后cAMP水平明显上调。因此，分别以100M吗啡作用SH-SY5Y细胞30分钟以及48小时作为急慢性吗啡细胞模型。
与动物实验结果一致，CCK-8可明显抑制急慢性吗啡作用后tau和MAP-2磷酸化水平的上调；为了明确tau和MAP-2磷酸化的机制，进一步观察了PKA，GSK-3β以及PP2A活性的变化，结果发现上述三种酶活性在急性吗啡作用后明显下调，而在慢性吗啡作用后均明显上调；PKA的特异抑制剂H-89可明显降低慢性吗啡诱导tau Ser262磷酸化水平的升高，而应用GSK-3β特异抑制剂SB216763后tau的Ser396位点以及MAP-2的Ser136和Thr1620/1623位点的磷酸化水平均明显下降。
10-6M CCK-8干预可明显翻转急性吗啡作用引起的PP2A活性的下降，急性CCK-8单独作用明显抑制PKA和GSK-3β的活性，但是对PP2A活性并无明显影响；CCK-8可明显抑制慢性吗啡引起的PKA和GSK-3β活性的增高，同时慢性单独作用也可明显降低PKA和GSK-3β的活性。
小结：外源性CCK-8可通过增加海马乙酰胆碱含量以及树突棘密度减轻吗啡致空间记忆的损害；CCK-8可通过下调tau和MAP-2的磷酸化水平调节吗啡诱导的突触可塑性变化。
结论：本文系统研究了外源性CCK-8对急慢性吗啡致空间记忆损害的影响以及突触可塑性机制，在整体和细胞水平观察了CCK-8对急慢性吗啡处理后tau和MAP-2表达及磷酸化改变的影响，并探讨了tau和MAP-2磷酸化的相关酶活性机制。得出以下结论：
1侧脑室给予CCK-8（0.01、0.1、1μg）可明显减轻吗啡依赖小鼠空间参考记忆的损害；训练前和测试前给予CCK-8（0.1、1μg）均可明显减轻急性吗啡诱导的空间参考记忆获得的损害。提示大剂量外源性CCK-8可通过自身对学习和记忆的影响和/或对阿片肽的拮抗作用参与了其减轻吗啡诱导空间记忆损害的过程。
2CCK-8（1μg）可通过增加海马乙酰胆碱含量以及树突棘密度减轻吗啡致空间记忆的损害，且通过下调tau和MAP-2的磷酸化水平调节吗啡诱导的突触可塑性变化。
3急性吗啡作用主要通过抑制PP2A活性上调tau和MAP-2磷酸化水平，而慢性吗啡作用则通过增强PKA和GSK-3β活性诱导了tau和MAP-2的磷酸化；急慢性CCK-8单独作用主要通过抑制PKA和/或GSK-3β活性使tau和MAP-2磷酸化水平下降；CCK-8干预可通过上调急性吗啡作用引起的PP2A活性下降及下调慢性吗啡引起的PKA和GSK-3β活性增高，抑制了吗啡诱导tau和MAP-2磷酸化水平的增高。
Long-term application of opioids can lead to tolerance and adiiction.Meanwhile, cognitive and learning and memory was impaired by opioidstreatment. Spatial learning and memory is a kind of scenes and events memory,and morphine dependence or acute morphine treatment could induce spatialmemory impairment. Cholecystokinin octopeptide (CCK-8), one of the mostefficient anti-opioid peptides, is widely spread in the central and peripheralnervous system, which play an important role in modulating memory processsuch as avoidance reaction, spatial identification and so on. However, theeffect of CCK-8on morphine induced memory impairment and its relatedmechanism is unclear.
Synaptic plasticity is the physiological basis of learning and memory, andspatial learning and memory impairment is closely related to the synapticplasticity change in hippocampus region. The skeletal system plays animportant role in regulating synaptic plasticity. Tau and MAP-2regulates thepre-synaptic and postsynaptic plasticity and steady-state plasticity of neuronsby affecting the stability of microtubules which are located in the axon anddendrites respectively. Study showed that phosphorylation state of tau andMAP-2was also participated in the learning and memory process. But,whether tau and MAP-2were responsible for the effect of CCK8on morphineinduced synaptic plasticity change is not clear.
We use Morris water maze to observe the effect of exogenous CCK8onspatial reference memory impairment in acute and chronic morphine-treatedmice. Then we aimed to clarify the role of skeleton associated protein ineffects of CCK-8on synaptic plasticity change induced by morphine toexplore the mechanism of CCK-8on memory impairment by morphine.
Part1: Effects of CCK-8on spatial memory in morphine-treated mice
Objective: We use Morris water maze to observe the effect of morphinedependence and acute morphine on spatial reference memory; different dosesof exogenous CCK-8were given before morphine to evaluate effect of CCK-8on spatial memory in morphine-treated mice; effect of exogenous CCK-8treatment alone on spatial reference memory was also observed.
Methods:①Morphine dependent model was established by increasingdoses manner (1-6days, morphine was subcutaneous injected at dose followed:20,40,60,80,100,100mg/kg, respectively,2times a day,12hours interval);different doses (0.001,0.01,0.1and1ug) of CCK-8was given by lateralventricle injection,2times a day at12hours interval. Morris water maze inthe next7days to adapt, training and testing, training and tests are conducted30minutes after drug injection. During this period, morphine100mg/kg orCCK-8were still given to mice; to observe effect of exogenous CCK-8onspatial reference memory in chronic morphine-treated mice, CCK-8was given30minutes before every morphine injection.②we adopted a2-day Morriswater maze model to assess acute drug treatment on spatial memory.1,5andor CCK-8(0.001,0.01,0.1and1μg, i.c.v)30minutes before training and testto assess effect of morphine or CCK-8on spatial reference memoryacquisition and retrieval respectively;10mg/kg morphine(i.p) was given30minutes before training, and different doses of CCK-8(0.001,0.01,0.001and1μg) were given30minutes before morphine or test to observe exogenousCCK-8on acute morphine induced spatial memory acquisition impairment.
Results:①552mice were included in the final statistical analyses.
②Chronic morphine significantly impaired spatial reference memory onthe probe test but did not affect the performance in place navigation trails;Spatial reference memory impairment by chronic morphine could delay to7days after morphine spontaneous withdrawal; CCK-8(0.1and1μg) alonesignificantly improved the spatial reference memory; CCK8(0.01,0.1and1μg) significantly improved the impairment of spatial reference memoryinduced by chronic morphine.
③Morphine (5and10mg/kg) treatment30minutes before training significantly impaired spatial reference memory acquisition in mice, whichshowed a poor performance in place navigation trails and probe test in watermaze experiment, but morphine (1,5, and10mg/kg) treatment30minutesbefore test had no effect on memory retrieval; CCK-8(0.01,0.01and1μg)treatment30minutes before training or CCK-8(0.1and1μg) before test couldpromote the acquisition and retrieval of spatial reference memory respectively;CCK-8(0.1and1μg) before training or test could significantly improveimpairment of spatial memory acquisition by morphine (10mg/kg) in mice,but CCK-8(0.001and0.01μg) had no obvious effect.
Summary:①This part of study found that chronic morphine obviouslyimpaired spatial reference memory, and the damage can be delay to7daysafter morphine withdrawal; CCK-8(0.01,0.1,1μg) could improve the spatialreference memory damage induced by chronic morphine; at the same time,CCK-8(0.1and1μg) alone could significantly improved the spatial referencememory in mice.
②Acute morphine significantly affected the spatial reference memoryacquisition in mice, but did not affect memory retrieval; CCK-8before thetraining or test significantly improved impairment of memory acquisitioninduced by morphine; CCK-8treatment alone could improved spatialreference memory acquisition or retrieval.
Part2: mechanism of CCK-8alleviating spatial memory impairment bymorphine
1effect of CCK-8on acetylcholine content and dendritic spine density inhippocampus of morphine-treated mice
Objective: Acetylcholine content and dendritic spine density change inhippocampus were observed to clarify the role of synaptic plasticity change inCCK-8on spatial memory in morphine-treated mice.
Methods: We established acute or chronic morphine mice model first,then LC-MS and Golgi staining were adopted to detect acetylcholine levelsand density of dendritic spines in morphine or CCK-8treatment.
Results:48mice were included in the final statistical analyses. Acute morphine significantly decreased the content of acetylcholine in thehippocampus, but acetylcholine content increased after chronic morphinetreatment; Acute or chronic CCK-8(1μg) could significantly increaseacetylcholine content in hippocampus; pre-injection of CCK-8(1μg) couldobviously reverse acetylcholine content decreased by acute morphine, but hadno obvious effect on chronic morphine. Chronic morphine significantlyreduced density of dendritic spines in the hippocampus; Chronic CCK-8(1μg)alone obviously increased density of dendritic spines in the hippocampus;Pre-injection of CCK-8(1μg) could obviously reversed effect of hronicmorphine on density of dendritic spines in hippocampus.
2effect of CCK-8on tau and MAP-2expression in hippocampus ofmorphine-treated mice
Objective: Microtubule associated protein tau and MAP-2expression inhippocampus were observed, in order to investigate the role of skeletonprotein system in synaptic plasticity changes.
Methods: Tau and MAP-2expression in hippocampus by morphine andCCK-8treatment were detected by RT-PCR and Western Blot.
Results:48mice were included in the final statistical analyses. Acutemorphine or CCK-8treatment alone did not affect tau and MAP-2expressionin hippocampal, pre-injection of CCK-8(1μg) could obviously reverse theeffect of acute morphine induced phosphorylation of tau Ser396, MAP-2Ser136and Thr1620/1623; phosphorylation of tau Ser262had no obviouschange after acute morphine treatment, and was increased by acute CCK-8treatment.
Pre-injection of CCK-8(1μg) could obviously reverse the effect chronicmorphine on tau and MAP-2expression-downregulation and phosphorylationup-regulation in hippocampal; chronic CCK-8(1μg) treatment had no effecton the expression of tau, but obviously up-regulated the expression of MAP-2,and deceased phosphorylation level of tau and MAP-2.
3mechanism of CCK-8downregulating morphine induced tau and MAP-2phosphorylation
Objective: On the basis of acute morphine and morphine chronic cellmodel is established, we focused on activity of kinase and phosphorylaserelated to tau and MAP-2phosphorylation, in order to clarify the mechanismsof tau and MAP-2phosphorylation by morphine or CCK-8treatment.
Methods: We observed intracellular cAMP level by time distinguishfluorescence detection, in order to confirm the acute and chronic morphinecell model was success established. Western Blot and enzyme activity kitswere used to detected tau and MAP-2phosphorylation and PKA, GSK-3βandPP2A activity changes.
Results: cAMP level in SH-SY5Y cells is decreased within3h andincreased after24h of morphine treatment; cAMP level obviouslyup-regulated by10M naloxone in SH-SY5Y cell treaed with100Mmorphine for48h. SH-SY5Y treated with100M morphine for30minutes or48hours as acute or chronic morphine cell model.
Cosistant with animal experiment, pre-treatment of CCK-8obviouslydecreased phosphorylation level of tau and MAP-2induced by acute orchronic morphine; to explore the mechanism of tau and MAP-2phosphorylation, PKA, GSK-3β and PP2A activity were detected. Resultsshowed that PKA, GSK-3β and PP2A activity were significantly decreased orincreased in acute or chronic morphine treatment SH-SY5Y cell; the PKAspecific inhibitors H-89could significantly reversed tau Ser262phosphorylation by chronic morphine, and GSK-3β specific inhibitorsSB216763significantly reversed phosphorylation of tau in Ser396and MAP-2in Ser136and Thr1620/1623.
Acute CCK-8could increase activity of PKA and decrease activity ofGSK-3β respectively, PP2A activity showed no obvious change; ChronicCCK-8could obviously decreased the activity of PKA and GSK-3β butincreased PP2A activity significantly. Pre-injection with10-6M of CCK-8could obviously reverse PP2A activity by acute morphine treatment, andreverse PKA and GSK-3β activity by chronic morphine treatment.
Summary: This part of the study indicated that exogenous CCK-8couldrelieve morphine induced changes in synaptic plasticity by regulatingacetylcholine content and dendritic spines density in hippocampus; the rationof phosphorylation and dephosphorylation level of tau and MAP-2might beparticipated in effect of CCK-8on morphine induced synaptic plasticitychange.
Conclusions: This study reveals the effect of exogenous CCK-8on acuteand chronic morphine-induced spatial reference memory impairment andsynaptic plasticity mechanism, effect of CCK-8on morphine-inducedphosphorylation of tau and MAP-2and its mechanism were observed inanimal and SH-SY5Y cell. We can reach the conclusion as follows:
1CCK-8(0.01,0.1,1μg) could improve the spatial reference memorydamage induced by chronic morphine; CCK-8(0.1and1μg) before thetraining or test significantly improved impairment of memory acquisitioninduced by acute morphine. High dose of CCK-8may improve spatialmemory loss by morphine through anti-opiod way and/or the effect onmemory regulation itself.
2Exogenous CCK-8(1μg) could relieve morphine induced changes insynaptic plasticity by regulating acetylcholine content and dendritic spinesdensity in hippocampus, and phosphorylation level of tau and MAP-2might be participated in effect of on morphine induced synaptic plasticitychanges.
3Acute morphine increased phosphorylation level of tau and MAP-2bydecreasing PP2A activity, PKA and GSK-3β might be major responsiblefor tau and MAP-2phosphorylation by chronic morphine treatment;10-6Mof CCK-8might decreased tau and MAP-2phosphorylation throughinhibiting PKA and/or GSK-3β activity; pre-injection with10-6M ofCCK-8could obviously reversed PP2A activity by acute morphinetreatment, and reversed PKA and GSK-3β activity by chronic morphinetreatment.
引文
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