本文選題：阿塞那平 + 奧氮平�。� 參考：《揚(yáng)州大學(xué)》2014年碩士論文

【摘要】：在常用的幾種抗精神病藥物中,奧氮平和利培酮在條件性回避模型和苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn)模型(兩種典型的抗精神病藥物模型)中產(chǎn)生敏感性效應(yīng)而氯氮平產(chǎn)生耐受性。阿塞那平(Asenapine)是一種用于治療精神分裂癥以及躁狂癥的非典型抗精神病藥物,它和其他非典型抗精神病藥物有共同的受體。但尚不清楚阿塞那平是否能產(chǎn)生敏感性或耐受性,也不清楚它產(chǎn)生的這種效應(yīng)能否作用于其他非典型抗精神病藥物(即交叉作用)。在本研究中,我們?cè)跅l件性回避反應(yīng)模型中或苯環(huán)己哌(3.20mg/kg)誘導(dǎo)的活動(dòng)亢進(jìn)模型中對(duì)成年SD大鼠反復(fù)注射阿塞那平(0.05,0.10及0.20mg/kg)5天,間隔兩天后給所有老鼠注射一個(gè)相同劑量的阿塞那平(0.10mg/kg),之后間隔兩天所有老鼠注射一個(gè)相同劑量的奧氮平(0.50mg/kg),然后再次間隔兩天后注射氯氮平(2.50mg/kg),在前5天的藥物使用階段(誘導(dǎo)階段),阿塞那平能有效的抑制回避反應(yīng)及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn),這種抑制呈劑量依賴(lài)性關(guān)系。在阿塞那平和奧氮平表達(dá)階段,藥物組比對(duì)照組呈現(xiàn)更低的回避反應(yīng)及活動(dòng)亢進(jìn)(敏感性)。在苯環(huán)己哌啶模型中也發(fā)現(xiàn)了氯氮平的敏感效應(yīng)。這些發(fā)現(xiàn)表明阿塞那平能夠產(chǎn)生敏感性效應(yīng),而且這種效應(yīng)能和奧氮平和氯氮平產(chǎn)生交叉敏感性,但氯氮平的交叉效應(yīng)略差。由于在這兩種模型中相比于氯氮平阿塞那平更類(lèi)似于奧氮平的作用,因此我們推測(cè),阿塞那平在治療作用和副作用方面相比于氯氮平更類(lèi)似于奧氮平。 在發(fā)現(xiàn)阿塞那平可以在成年大鼠產(chǎn)生較長(zhǎng)時(shí)間的敏感性作用之后。我們又研究了阿塞那平在青春期發(fā)育期間的敏感性以及當(dāng)這些大鼠成年后與抗精神病藥物作用相關(guān)的3種蛋白(即腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體和AFosB)的改變。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)并在條件性回避模型或及苯環(huán)己哌啶(2.00mg/kg)誘導(dǎo)的活動(dòng)亢進(jìn)模型中測(cè)試5天。待他們成年后(出生后76天)給所有大鼠注射阿塞那平(0.10mg/kg)并測(cè)試其敏感性。實(shí)驗(yàn)完成1天后取大鼠前額葉皮質(zhì)、紋狀體和海馬組織并用Western blotting檢測(cè)這些腦組織中腦源性神經(jīng)營(yíng)養(yǎng)因子,多巴胺D2受體和AFosB的改變。在青春期大鼠,反復(fù)阿塞那平處理產(chǎn)生了持久的劑量依賴(lài)性的對(duì)條件性回避反應(yīng)以及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn)的抑制作用。在大鼠成年后的敏感性測(cè)試中,相對(duì)于空白對(duì)照組,阿塞那平(0.10,0.20mg/kg)產(chǎn)生更明顯的抑制效應(yīng)。但是各組之間腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體和ΔFosB的表達(dá)并未發(fā)現(xiàn)明顯的差異。該實(shí)驗(yàn)結(jié)果表明盡管青春期短時(shí)間給予阿塞那平治療可以誘導(dǎo)出敏感性,而且這種敏感性可以持續(xù)持續(xù)到成年期,但這種敏感性的保持可能并不是由腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體和△FosB介導(dǎo)的。 一、反復(fù)阿塞那平治療在兩種臨床前抗精神病模型中的敏感性 目的阿塞那平能否產(chǎn)生敏感性,如果能,這種敏感性能否交叉作用于奧氮平和氯氮平。 方法使用條件性回避模型及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn)模型,采用短時(shí)(5天)連續(xù)藥物干預(yù),之后給予相對(duì)低劑量的阿塞那平,檢測(cè)不同組之間回避反應(yīng)及活動(dòng)亢進(jìn)的抑制狀況。 結(jié)果在前5天的藥物誘導(dǎo)階段,阿塞那平能有效的抑制回避反應(yīng)及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn),這種抑制呈劑量依賴(lài)關(guān)系。在阿塞那平和奧氮平表達(dá)階段,藥物組比對(duì)照組呈現(xiàn)更低的回避反應(yīng)及活動(dòng)亢進(jìn)(敏感性)。在苯環(huán)己哌啶模型中也發(fā)現(xiàn)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機(jī)制 目的阿塞那平在青春期的敏感性能否持續(xù)到成年以及其分子機(jī)制 方法使用條件性回避模型及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn)模型,在大鼠青春期短時(shí)(5天)連續(xù)藥物干預(yù),待其成年后相對(duì)低劑量阿塞那平處理,檢測(cè)不同組之間回避反應(yīng)及活動(dòng)亢進(jìn)的抑制狀況,之后檢測(cè)大鼠前額葉皮質(zhì)、紋狀體及海馬組織中腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體及ΔFosB水平。 結(jié)果在青春期大鼠,重復(fù)阿塞那平處理產(chǎn)生了持久和劑量依賴(lài)性對(duì)條件性回避反應(yīng)以及苯環(huán)己哌啶誘導(dǎo)的活動(dòng)亢進(jìn)的抑制作用。在大鼠成年后的敏感性測(cè)試中,相對(duì)于空白對(duì)照組,阿塞那平(0.10,0.20mg/kg)產(chǎn)生更明顯的抑制作用。但是各組之間腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體和ΔFosB的表達(dá)并未發(fā)現(xiàn)明顯的差異。 結(jié)論 1.阿塞那平能夠產(chǎn)生敏感性效應(yīng),而且這種效應(yīng)能和奧氮平和氯氮平產(chǎn)生交叉敏感性,但氯氮平的交叉效應(yīng)略差。由于在這兩種模型中相比于氯氮平阿塞那平更類(lèi)似于奧氮平的作用,我們推測(cè),阿塞那平在治療作用和副作用方面相比于氯氮平更類(lèi)似于奧氮平。 2.青春期短時(shí)間給予阿塞那平治療可以誘導(dǎo)出敏感性,而且這種敏感性可以持續(xù)到成年期,但這種敏感性的保持可能并不是由腦源性神經(jīng)營(yíng)養(yǎng)因子、多巴胺D2受體和ΔFosB介導(dǎo)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.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R965

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 胡玲;沈浩;;艾塞那肽治療肥胖2型糖尿病23例臨床分析[J];中國(guó)實(shí)用內(nèi)科雜志;2012年04期

2 李可心;李春花;李遠(yuǎn)征;王虹;;艾塞那肽治療肥胖2型糖尿病64例療效觀察[J];中國(guó)社區(qū)醫(yī)師(醫(yī)學(xué)專(zhuān)業(yè));2012年36期

3 許玲美;徐智儒;檀瓊;肖峰;趙莎莎;秦燕;;2型糖尿病治療藥物艾塞那肽及其開(kāi)發(fā)[J];世界臨床藥物;2013年07期

4 張穎;曾朝陽(yáng);劉旭;華思文;;艾塞那肽治療2型糖尿病的臨床觀察[J];山西醫(yī)科大學(xué)學(xué)報(bào);2012年02期

5 金毅;;艾塞那肽治療2型糖尿病患者的療效觀察[J];中外醫(yī)療;2012年21期

6 章玉華;蔡祥增;王雷;王德震;;艾塞那肽治療2型糖尿病臨床觀察[J];臨床合理用藥雜志;2012年31期

7 楊璐;謝文秀;曹悅鞍;彭朝勝;夏菁;張文洛;;艾塞那肽治療肥胖2型糖尿病臨床觀察[J];轉(zhuǎn)化醫(yī)學(xué)雜志;2012年02期

8 楊巖斌;;艾塞那肽注射液在2型糖尿病中的治療效果研究[J];中外醫(yī)學(xué)研究;2012年32期

9 龐敏;張紅軍;;艾塞那肽治療肥胖2型糖尿病療效觀察[J];中國(guó)社區(qū)醫(yī)師(醫(yī)學(xué)專(zhuān)業(yè));2013年10期

10 莫澤緯;陳開(kāi)寧;;艾塞那肽治療不同體質(zhì)指數(shù)2型糖尿病患者的療效及安全性[J];實(shí)用醫(yī)學(xué)雜志;2013年16期

相關(guān)會(huì)議論文 前10條

1 丁麗;張紹維;趙文洲;羅晶;;艾塞那肽對(duì)人臍靜脈內(nèi)皮細(xì)胞內(nèi)皮型一氧化氮合酶活性和表達(dá)的影響[A];中華醫(yī)學(xué)會(huì)第十二次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2013年

2 胡碧煌;;從巨蜥毒液中開(kāi)發(fā)的新藥——艾塞那肽[A];第九屆中國(guó)生物毒素學(xué)術(shù)研討會(huì)論文摘要[C];2009年

3 陳若然;梁琳瑯;王健美;王宇;;艾塞那肽對(duì)載脂蛋白E基因敲除小鼠動(dòng)脈粥樣硬化模型中動(dòng)脈病變的作用[A];中華醫(yī)學(xué)會(huì)第十二次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2013年

4 陳晶;張弛;陳丹丹;李華珠;楊曉春;周桂蓮;王敏;熊璞;王霞;劉瑛;;艾塞那肽治療對(duì)2型糖尿病患者緩解期的影響[A];中華醫(yī)學(xué)會(huì)第十次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2011年

5 吳靜;李駿;王全勝;劉曉麗;倪衛(wèi)惠;邵曉麗;祝保艷;;艾塞那肽對(duì)2型糖尿病臨床療效觀察[A];中華醫(yī)學(xué)會(huì)第二屆糖尿病及性腺疾病學(xué)術(shù)會(huì)議論文集[C];2012年

6 楊威;鄭麗麗;李沖;李珊;王志芳;王小紅;;艾塞那肽對(duì)高糖誘導(dǎo)的內(nèi)皮細(xì)胞凋亡的影響及其作用機(jī)制[A];中華醫(yī)學(xué)會(huì)第十二次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2013年

7 周理蘭;韓萍;;艾塞那肽對(duì)球囊損傷髂總動(dòng)脈大鼠血管炎癥作用的活體研究[A];中華醫(yī)學(xué)會(huì)第十一次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2012年

8 胡晶;馬永文;;艾塞那肽在肥胖2型糖尿病患者中療效和安全性的臨床觀察[A];中華醫(yī)學(xué)會(huì)糖尿病學(xué)分會(huì)第十六次全國(guó)學(xué)術(shù)會(huì)議論文集[C];2012年

9 劉賽;張弛;陳丹丹;李華珠;楊曉春;周桂蓮;王敏;熊璞;王霞;陳晶;劉瑛;;艾塞那肽治療對(duì)血壓正常2型糖尿病患者血壓的影響[A];中華醫(yī)學(xué)會(huì)第十次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2011年

10 王琛;李衛(wèi)虹;王廣;王海寧;馮新恒;高洪偉;洪天配;;艾塞那肽對(duì)2型糖尿病患者冠狀動(dòng)脈內(nèi)皮功能的影響[A];中華醫(yī)學(xué)會(huì)第十一次全國(guó)內(nèi)分泌學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2012年

相關(guān)重要報(bào)紙文章 前7條

1 ;美國(guó)再次警告艾塞那肽注射液風(fēng)險(xiǎn)[N];健康報(bào);2009年

2 欣文;美國(guó)再次警告艾塞那肽注射液的急性胰腺炎風(fēng)險(xiǎn)[N];中國(guó)醫(yī)藥報(bào);2009年

3 加拿大衛(wèi)生部網(wǎng)站;加拿大警告與艾塞那肽相關(guān)的胰腺癌風(fēng)險(xiǎn)[N];中國(guó)醫(yī)藥報(bào);2013年

4 二炮總醫(yī)院內(nèi)分泌科 李全民;艾塞那肽好在哪?[N];健康時(shí)報(bào);2011年

5 駐滬記者 魏峗;新藥也需伯樂(lè)[N];醫(yī)藥經(jīng)濟(jì)報(bào);2009年

6 靖九江;禮來(lái)GLP—1受體激動(dòng)劑百泌達(dá)進(jìn)入中國(guó)[N];中國(guó)醫(yī)藥報(bào);2009年

7 記者 陳國(guó)東;禮來(lái)糖尿病新藥百泌達(dá)進(jìn)入中國(guó)[N];醫(yī)藥經(jīng)濟(jì)報(bào);2009年

相關(guān)碩士學(xué)位論文 前10條

1 田洪斌;注射用艾塞那肽凍干粉針劑的研究[D];吉林大學(xué);2008年

2 武俊紫;艾塞那肽對(duì)非酒精性脂肪肝病的治療作用研究[D];昆明理工大學(xué);2014年

3 秦榮印;反復(fù)阿塞那平治療在兩種臨床前抗精神病模型中的敏感性及其分子基礎(chǔ)[D];揚(yáng)州大學(xué);2014年

4 陳若然;艾塞那肽對(duì)載脂蛋白E基因敲除小鼠動(dòng)脈粥樣硬化模型中動(dòng)脈病變的影響[D];遼寧醫(yī)學(xué)院;2013年

5 蘇春;艾塞那肽對(duì)2型糖尿病患者炎癥因子、脂聯(lián)素及瘦素的影響[D];廣西醫(yī)科大學(xué);2012年

6 張?jiān)S;降糖藥艾塞那肽和利拉魯肽的固相合成及艾塞那肽的藥效學(xué)評(píng)價(jià)[D];泰山醫(yī)學(xué)院;2012年

7 韓文彪;艾塞那肽治療2型糖尿病療效的初步觀察[D];青海大學(xué);2011年

8 李亞娟;艾塞那肽治療肥胖2型糖尿病的臨床研究[D];蘇州大學(xué);2013年

9 于佳一;艾塞那肽合成方法學(xué)研究[D];吉林大學(xué);2006年

10 唐華勇;艾塞那肽誘發(fā)大鼠慢性胰腺炎發(fā)生機(jī)制的初步實(shí)驗(yàn)研究[D];中南大學(xué);2010年

，

本文編號(hào)：1954071