苯环己哌啶致食蟹猴gamma震荡异常及多巴胺能药物对gamma震荡的影响

发布时间：2018-07-11 16:54

本文选题：精神分裂症 + gamma震荡　；参考：《昆明医科大学》2017年硕士论文

【摘要】：[背景与目的]精神分裂症被认为是一种神经系统结构功能发育异常及变性所致疾病,常以思想和行为不协调、妄想、幻觉等阳性症状及主动性降低、社会功能减退、情感淡漠等阴性症状为表现。其中认知功能障碍是精神分裂症的核心缺损症状。许多实验表明,谷氨酸能(Glutamate,Glu)与多巴胺能(dopamine, DA)神经递质功能紊乱造成神经网络兴奋-抑制失平衡,导致了精神分裂症阳性症状与阴性症状并存的结果。这两类神经元能够通过γ-氨基丁酸(γ-aminobutyric acid,GABA)能中间神经元相互作用相互影响。GABA能中间神经元从结构、生理功能及分子特性上分为许多种亚型,其中小清蛋白(Parvalbumin, PV)阳性的GABA能中间神经元的异常放电引起gamma震荡异常,导致认知功能受损。gamma震荡在神经生理功能中扮演着重要角色,比如选择注意力、各种感觉的加工、感知觉特性的整合以及工作记忆的储存与取回等,而这些功能的损害恰好是精神分裂症的核心症状。与健康人群相比,异常的前额叶gamma震荡常常可以在精神分裂症患者身上检测出来。目前认为,前额叶gamma震荡异常虽不是精神分裂症的特有现象,但其对于该疾病的诊断、治疗以及预后评估均有重要意义。许多实验证实了应用N-甲基-D-天冬氨酸盐(N-methyl-D-aspartate, NMDA)受体拮抗剂或DA受体激动剂/拮抗剂后能使前额叶gamma震荡能量异常,但结论并不一致。苯环己哌啶(Phencyclidine,PCP)是一种非特异性NMDA受体拮抗剂,能够较好的模拟精神分裂症样症状。目前研究特定状态下非人灵长类前额叶gamma震荡的实验较少。我们以慢性PCP食蟹猴作为主要研究对象,进一步验证DA能及Glu能神经递质对前额叶gamma震荡的影响。[方法]实验对象为随机挑选的4只正常成年雌性石蟹猴、6只长期注射PCP的成年雌性食蟹猴作为实验组。采用头皮植入电极记录装置,电极分别置于双侧前额部(F3、F4),地线接双侧眉弓中心(D),参考线接单侧耳垂(A),给予条件测量范式(Conditioning-testing paradigm)的双声刺激(双声间隔时间为500ms,每对双声刺激之间间隔为5-10s的重复性双声刺激模式,声音强度为75 dB,背景噪音:45dB)诱发脑电活动来检测。首先对比正常对照组食蟹猴与慢性PCP实验组未注药双侧前额叶基线gamma震荡功率是否有差异。再分别给予3种不同剂量的DA受体激动剂溴隐亭(0.313 mg/kg,0.625 mg/kg,1.25 mg/kg)及3种不同剂量DA受体拮抗剂氟哌啶醇(0.001 mg/kg,0.01 mg/kg,0.05 mg/kg)后,分时段记录脑电信号(0-30min、30-60min),离线提取、计算食蟹猴双侧前额叶gamma震荡功率,并进行统计学分析。[结果]1.实验一(正常对照组与慢性PCP组的基线比较);慢性PCP组食蟹猴双侧前额叶基线gamma震荡功率值较正常对照组显著下降。2.实验二(溴隐亭组,Bromocriptine):低剂量溴隐亭(0.312mg/kg)使慢性PCP食蟹猴左侧前额叶gamma震荡功率先显著升高再显著降低;使右侧前额叶gamma震荡功率在注药后30-60min内较注药后0-30min明显下降。中等剂量组溴隐亭(0. 625mg/kg)对慢性PCP食蟹猴双侧前额叶gamma震荡功率无显著影响。高剂量组溴隐亭(1. 25mg/kg)对慢性PCP食蟹猴双侧前额叶gamma震荡功率无显著影响。3.实验三(氟哌啶醇组,Haloperidol):低剂量氟哌啶醇(0.001mg/kg)对慢性PCP食蟹猴双侧前额叶gamma震荡功率未造成显著影响。中等剂量氟哌啶醇(0. 01mg/kg)对慢性PCP食蟹猴双侧前额叶gamma震荡功率未造成显著影响。高剂量氟哌啶醇(0.05mg/kg)使慢性PCP食蟹猴较未注药时左侧前额叶gamma震荡功率显著升高;右侧前额叶在注药后0-30min内gamma功率较未注药时显著升高。[结论]长期应用NMDA受体拮抗剂PCP能诱导食蟹猴双侧前额叶gamma震荡能量下降。低剂量DA受体激动剂溴隐亭能使慢性PCP食蟹猴双侧前额叶gamma震荡功率呈先升高再降低的趋势,可能与该药物在不同时间段主要作用的部位不同引起。高剂量DA受体拮抗剂氟哌啶醇能增加慢性PCP食蟹猴模型双侧前额叶gamma震荡功率,可能改善精神分裂症患者认知相关症状。表明DA系统功能紊乱对精神分裂症的认知障碍起着一定的作用,并且DA、Glu及GABA三者平衡失调构成了精神分裂症的病理生理基础。
[Abstract]:[background and purpose] schizophrenia is considered to be a disease caused by dysfunctional dysplasia and degeneration of the nervous system. It often shows negative symptoms such as disharmony of thought and behavior, delusions, hallucinations and other positive symptoms, social dysfunction, indifference and other negative symptoms. Cognitive dysfunction is the core defect of schizophrenia. Symptoms. Many experiments show that Glutamate (Glu) and dopamine (dopamine, DA) neurotransmitter dysfunction cause nerve network excitation - inhibition of imbalance, which results in the coexistence of both positive and negative symptoms of schizophrenia. These two types of neurons can be able to use gamma aminobutyric acid (gamma -aminobutyric acid, GABA) to be in the middle God. The interaction of.GABA can be divided into many subtypes from the structure, physiological function and molecular characteristics, in which the abnormal discharge of the Parvalbumin, PV positive GABA intermediate neurons causes the gamma oscillation to be abnormal, causing the cognitive impairment to play an important role in the neurophysiological function. Color, such as the choice of attention, the processing of various sensations, the integration of sensory perception and the storage and retrieval of working memory, and the impairment of these functions is the core symptom of schizophrenia. Compared with the healthy population, abnormal prefrontal gamma concussion can often be detected in the patients with seminal schizophrenia. Although abnormal gamma turbulence in the frontal lobe is not a characteristic of schizophrenia, it is of great significance for the diagnosis, treatment and prognosis of the disease. Many experiments have proved that the application of N- methyl -D- aspartate (N-methyl-D-aspartate, NMDA) receptor antagonist or DA receptor agonist / antagonist can make the gamma concussion energy in the prefrontal lobe Abnormal, but the conclusion is not consistent. Phencyclidine (PCP) is a nonspecific NMDA receptor antagonist, which can better simulate schizophrenia like symptoms. At present, there are few experiments on the gamma concussion of non human primate prefrontal lobes under specific state. We use chronic PCP food cynomolgus as the main research object, and further verify DA The effects of Glu neurotransmitters on the gamma concussion of prefrontal lobes. [Methods] 4 normal adult female cynomolgus monkeys were selected randomly, and 6 adult female cynomolgus monkeys with long-term injection of PCP were used as the experimental group. The electrodes were implanted into the electrode recording device of the scalp implantation, the electrodes were placed in the anterior frontal part (F3, F4), and the ground wire was connected to the bilateral eyebrow bow Center (D). One side lobe of the ear lobe (A) was followed by a double acoustic stimulation of the conditional measurement paradigm (Conditioning-testing paradigm) (a double sound interval of 500ms, a double sound stimulation mode of 5-10S between each pair of stimuli, the sound intensity of 75 dB, the background noise: 45dB) induced electroencephalogram detection. First, compared with the normal control group, the cynomolgus monkeys were compared with the normal control group. 3 different doses of DA receptor agonist bromocriptine (0.313 mg/kg, 0.625 mg/kg, 1.25 mg/kg) and 3 different doses of DA receptor antagonist haloperidol (0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg) were given separately, and the EEG signals were recorded at a period of time (0-30min). (0-30min), the EEG signals were recorded in the chronic PCP test group. 30-60min), off-line extraction, calculation of gamma shock power of bilateral prefrontal lobes in cynomolgus, and statistical analysis. [results]1. Experiment 1 (comparison between normal control group and baseline of chronic PCP group); the value of gamma shock power of bilateral prefrontal baseline in chronic PCP group was significantly lower than that in normal group,.2. experiment two (bromocriptine group, Bromocriptine): The low dose of bromocriptine (0.312mg/kg) significantly increased the gamma shock power of the left prefrontal lobe of chronic PCP cynomolgus and then decreased significantly, and the gamma concussion power of the right prefrontal lobe decreased significantly in 30-60min after injection than after injection of the drug. The moderate dose group of bromocriptine (0. 625mg/kg) did not have the power of gamma concussion in the bilateral prefrontal cortex of chronic PCP cynomolgus monkey Significant effect. The high dose group of bromocriptine (1. 25mg/kg) had no significant effect on the gamma concussion power of the bilateral prefrontal cortex of chronic PCP cynomolgus,.3. experiment three (haloperidol group, Haloperidol): low dose haloperidol (0.001mg/kg) had no significant effect on the gamma concussion power of bilateral prefrontal cortex of chronic PCP cynomolgus macaque. Middle dose haloperidol (0. 01mg/kg). There was no significant effect on the gamma concussion power of the bilateral prefrontal cortex of chronic PCP cynomolgus. High dose of haloperidol (0.05mg/kg) increased the gamma shock power of the left prefrontal lobe of the chronic PCP cynomolgus, while the right prefrontal lobe was significantly higher in the gamma power in 0-30min after the injection. [Conclusion] the long-term application of NMDA receptor antagonism Anti PCP can induce the decrease of gamma shock energy in the prefrontal cortex of cynomolgus. The low dose DA receptor agonist bromocriptine can increase the gamma oscillation power in the bilateral prefrontal cortex of chronic PCP cynomolgus, and then decrease. It may be different from the main part of the drug in different time periods. The high dose DA receptor antagonist haloperidol can be used. The increase of gamma shock power in the bilateral prefrontal frontal lobes of the chronic PCP cynomolgus monkey model may improve the cognitive related symptoms of schizophrenia, indicating that the dysfunction of the DA system plays a certain role in the cognitive impairment of schizophrenia, and the imbalance of DA, Glu and GABA constitutes the pathophysiological basis of schizophrenia.
【学位授予单位】：昆明医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.3

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