反复阿塞那平治疗在两种临床前抗精神病模型中的敏感性及其分子基础

发布时间：2018-05-30 05:17

本文选题：阿塞那平 + 奥氮平　；参考：《扬州大学》2014年硕士论文

【摘要】：在常用的几种抗精神病药物中,奥氮平和利培酮在条件性回避模型和苯环己哌啶诱导的活动亢进模型(两种典型的抗精神病药物模型)中产生敏感性效应而氯氮平产生耐受性。阿塞那平(Asenapine)是一种用于治疗精神分裂症以及躁狂症的非典型抗精神病药物,它和其他非典型抗精神病药物有共同的受体。但尚不清楚阿塞那平是否能产生敏感性或耐受性,也不清楚它产生的这种效应能否作用于其他非典型抗精神病药物(即交叉作用)。在本研究中,我们在条件性回避反应模型中或苯环己哌(3.20mg/kg)诱导的活动亢进模型中对成年SD大鼠反复注射阿塞那平(0.05,0.10及0.20mg/kg)5天,间隔两天后给所有老鼠注射一个相同剂量的阿塞那平(0.10mg/kg),之后间隔两天所有老鼠注射一个相同剂量的奥氮平(0.50mg/kg),然后再次间隔两天后注射氯氮平(2.50mg/kg),在前5天的药物使用阶段(诱导阶段),阿塞那平能有效的抑制回避反应及苯环己哌啶诱导的活动亢进,这种抑制呈剂量依赖性关系。在阿塞那平和奥氮平表达阶段,药物组比对照组呈现更低的回避反应及活动亢进(敏感性)。在苯环己哌啶模型中也发现了氯氮平的敏感效应。这些发现表明阿塞那平能够产生敏感性效应,而且这种效应能和奥氮平和氯氮平产生交叉敏感性,但氯氮平的交叉效应略差。由于在这两种模型中相比于氯氮平阿塞那平更类似于奥氮平的作用,因此我们推测,阿塞那平在治疗作用和副作用方面相比于氯氮平更类似于奥氮平。在发现阿塞那平可以在成年大鼠产生较长时间的敏感性作用之后。我们又研究了阿塞那平在青春期发育期间的敏感性以及当这些大鼠成年后与抗精神病药物作用相关的3种蛋白(即脑源性神经营养因子、多巴胺D2受体和AFosB)的改变。青春期SD大鼠(出生后43-48天)首次接受阿塞那平(0.05,0.10,0.20mg/kg)并在条件性回避模型或及苯环己哌啶(2.00mg/kg)诱导的活动亢进模型中测试5天。待他们成年后(出生后76天)给所有大鼠注射阿塞那平(0.10mg/kg)并测试其敏感性。实验完成1天后取大鼠前额叶皮质、纹状体和海马组织并用Western blotting检测这些脑组织中脑源性神经营养因子,多巴胺D2受体和AFosB的改变。在青春期大鼠,反复阿塞那平处理产生了持久的剂量依赖性的对条件性回避反应以及苯环己哌啶诱导的活动亢进的抑制作用。在大鼠成年后的敏感性测试中,相对于空白对照组,阿塞那平(0.10,0.20mg/kg)产生更明显的抑制效应。但是各组之间脑源性神经营养因子、多巴胺D2受体和ΔFosB的表达并未发现明显的差异。该实验结果表明尽管青春期短时间给予阿塞那平治疗可以诱导出敏感性,而且这种敏感性可以持续持续到成年期,但这种敏感性的保持可能并不是由脑源性神经营养因子、多巴胺D2受体和△FosB介导的。一、反复阿塞那平治疗在两种临床前抗精神病模型中的敏感性目的阿塞那平能否产生敏感性,如果能,这种敏感性能否交叉作用于奥氮平和氯氮平。方法使用条件性回避模型及苯环己哌啶诱导的活动亢进模型,采用短时(5天)连续药物干预,之后给予相对低剂量的阿塞那平,检测不同组之间回避反应及活动亢进的抑制状况。结果在前5天的药物诱导阶段,阿塞那平能有效的抑制回避反应及苯环己哌啶诱导的活动亢进,这种抑制呈剂量依赖关系。在阿塞那平和奥氮平表达阶段,药物组比对照组呈现更低的回避反应及活动亢进(敏感性)。在苯环己哌啶模型中也发现了氯氮平的抑制作用。二、青春期到成年期的阿塞那平敏感性及其分子机制目的阿塞那平在青春期的敏感性能否持续到成年以及其分子机制方法使用条件性回避模型及苯环己哌啶诱导的活动亢进模型,在大鼠青春期短时(5天)连续药物干预,待其成年后相对低剂量阿塞那平处理,检测不同组之间回避反应及活动亢进的抑制状况,之后检测大鼠前额叶皮质、纹状体及海马组织中脑源性神经营养因子、多巴胺D2受体及ΔFosB水平。结果在青春期大鼠,重复阿塞那平处理产生了持久和剂量依赖性对条件性回避反应以及苯环己哌啶诱导的活动亢进的抑制作用。在大鼠成年后的敏感性测试中,相对于空白对照组,阿塞那平(0.10,0.20mg/kg)产生更明显的抑制作用。但是各组之间脑源性神经营养因子、多巴胺D2受体和ΔFosB的表达并未发现明显的差异。结论 1.阿塞那平能够产生敏感性效应,而且这种效应能和奥氮平和氯氮平产生交叉敏感性,但氯氮平的交叉效应略差。由于在这两种模型中相比于氯氮平阿塞那平更类似于奥氮平的作用,我们推测,阿塞那平在治疗作用和副作用方面相比于氯氮平更类似于奥氮平。 2.青春期短时间给予阿塞那平治疗可以诱导出敏感性,而且这种敏感性可以持续到成年期,但这种敏感性的保持可能并不是由脑源性神经营养因子、多巴胺D2受体和ΔFosB介导的。
[Abstract]:In several commonly used antipsychotic drugs, olanzapine and risperidone produce sensitivity effects in the conditioned avoidance model and the hyperactivity model (two typical antipsychotic models) induced by the conditioned avoidance model, and clozapine is tolerable. Asanapine (Asenapine) is a kind of treatment for schizophrenia and mania. Atypical antipsychotic drugs have a common receptor with other atypical antipsychotics. But it is not clear whether asanatpine can produce sensitivity or tolerance, nor is it possible to act on other atypical antipsychotic drugs (cross effects). In this study, we are in a conditional avoidance. In the model or 3.20mg/kg induced hyperactivity model, the adult SD rats were repeatedly injected with anazapine (0.05,0.10 and 0.20mg/kg) for 5 days, and a same dose of azinapine (0.10mg/kg) was injected into all rats two days after the interval. After two days, the rats were injected with the same dose of olanzapine (0.50mg/kg). Clozapine (2.50mg/kg) was injected two days later. At the first 5 days of drug use (induction stage), asanapine could effectively inhibit the avoidance response and the hyperactivity of benzpiperidine induced hyperactivity. This inhibition was in a dose-dependent manner. In the anasanapine and orzapine stages, the drug group showed lower avoidance than the control group. Reaction and hyperactivity (sensitivity). The sensitive effect of clozapine was also found in the phenyl piperidine model. These findings suggest that anzapapine can produce sensitivity effects, and this effect can produce cross sensitivity with olanzapine and clozapine, but the cross effect of clozapine should be slightly worse. Compared to chloro nitrogen in these two models, The level of aspirin is more similar to that of olanzapine. Therefore, we hypothesized that the treatment of aninapine is more similar to olanzapine in the treatment and side effects than clozapine.
We also studied the sensitivity of anananpine during puberty and the changes in the 3 proteins associated with antipsychotic drugs (brain derived neurotrophic factor, dopamine D2 receptor and AFosB) in adult rats. SD rats (43-48 days after birth) were first received 0.05,0.10,0.20mg/kg (43-48 days after birth) and tested for 5 days in a conditioned avoidance model or a hyperactivity model induced by 2.00mg/kg. After they were adult (76 days after birth), all rats were injected with Arnold Na Ping (0.10mg/kg) and tested for their sensitivity. The experiment was completed for 1 days. The prefrontal cortex, striatum and hippocampus were taken and Western blotting was used to detect the changes of brain derived neurotrophic factor, dopamine D2 receptor and AFosB in these brain tissues. In puberty rats, repeated adrenasin treatment produced a prolonged dose dependent conditioned avoidance response and the activity induced by phenyl piperidine. The inhibitory effect of hyperactivity. In the adult sensitivity test, 0.10,0.20mg/kg produced a more obvious inhibitory effect compared to the blank control group. However, the expression of brain derived neurotrophic factor, dopamine D2 receptor and delta FosB was not significantly different between each group. The sensitivities can be induced and the sensitivity can continue to adulthood, but this sensitivity may not be mediated by brain derived neurotrophic factors, dopamine D2 receptors and delta FosB.
I. sensitivity of repeated treatment with two patients with preclinical antipsychotic models.
Objective whether sensenpine can produce sensitivity, if so, whether this sensitivity can cross the role of olanzapine and clozapine.
Methods the conditioned avoidance model and the hyperactivity model induced by benzpiperidine were used. A short time (5 day) continuous drug intervention was used, and a relatively low dose of asaccin was given to detect the inhibition of avoidance and hyperactivity between different groups.
Results in the first 5 days of the drug induction phase, asanapine could effectively inhibit the avoidance response and the hyperactivity of benzathperidine induced hyperactivity. This inhibition was dose-dependent. In the anasanapine and olanzapine stage, the drug group showed lower avoidance and hyperactivity (sensitivity) than the control group. The inhibitory effect of clozapine was found.
Two, the sensitivity and molecular mechanism of the age of adolescence to adulthood.
Objective can sensenpine's sensitivity to adolescence extend to adulthood and its molecular mechanism?
Methods the conditioned avoidance model and the hyperactivity model induced by benzropiperidine were used to intervene in the rats' puberty (5 days). The inhibition of the avoidance response and hyperactivity of the hyperactivity between the different groups was detected and the prefrontal cortex, the striatum and the hippocampus were detected. Midbrain derived neurotrophic factor, dopamine D2 receptor and delta FosB level.
Results in puberty rats, repeated asnpine treatment produced a prolonged and dose-dependent inhibition of conditioned avoidance responses and hyperactivity of pyridine induced hyperactivity. In the sensitivity test of adult rats, 0.10,0.20mg/kg produced a more obvious inhibitory effect than the blank control group. There was no significant difference in the expression of brain-derived neurotrophic factor, dopamine D2 receptor and delta FosB between groups.
conclusion
1. ananapine can produce a sensitivity effect, and this effect can have cross sensitivity to olanzapine and clozapine, but the cross effect of clozapine is slightly worse. As compared to olanzapine in these two models, we speculate that the effect and side effects of anzapine are compared to that in the treatment and side effects. Clozapine is more similar to olanzapine.
2. the sensitivity can be induced by the treatment of a short period of adolescence, and the sensitivity can last to adulthood, but this sensitivity may not be mediated by the brain derived neurotrophic factor, dopamine D2 receptor and delta FosB.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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