本文選題：條件躲避反射模型 + PCP模型�。� 參考：《南京中醫(yī)藥大學》2017年碩士論文

【摘要】：精神分裂癥是一組具有感知,情感,行為,思維等多方面障礙的精神疾病。該病以對現(xiàn)實的扭曲,伴隨幻覺和妄想以及思維語言功能的逐步惡化為特征,是造成個人和社會巨大經(jīng)濟負擔的較常見的中樞神經(jīng)系統(tǒng)疾病之一。近些年來,在兒童和青少年人群中使用抗精神病藥物的患者逐年增多,美國一項研究顯示,僅在1993至2002年間,使用抗精神病藥物的人群中年齡小于等于20歲的人次增加了約6倍。2004至2005年間,兒童和青少年使用抗精神病藥物的比例由1996至1997年間的7%增長至15%,其中90%以上是非典型抗精神病藥物。目前,關(guān)于接受抗精神病藥物治療的兒童和青少年患者的研究多集中在觀察藥物療效,不良反應(yīng)等方面,缺乏關(guān)于抗精神病藥物對此年齡階段的患者中樞神經(jīng)系統(tǒng)的影響以及行為學上改變的研究。研究表明,處于青春期的個體對于精神類藥物的反應(yīng)可能更加敏感,因為該時期是中樞神經(jīng)系統(tǒng)發(fā)育的重要階段。前臨床研究發(fā)現(xiàn)該時期前額葉皮層,紋狀體,海馬等部位突觸連接和受體密度,多巴胺以及五羥色胺系統(tǒng)等會經(jīng)歷巨大的成熟過程。該時期的藥物干預(yù)可以改變大腦的結(jié)構(gòu)和功能,且這種改變通常是持久的,不僅影響兒童和青少年患者大腦和行為的改變,同樣會影響個體成年后對藥物的反應(yīng)。動物實驗研究結(jié)果也發(fā)現(xiàn):給予青春期的大鼠抗精神病藥物干預(yù),會改變大鼠腦內(nèi)諸多神經(jīng)受體的表達,包括多巴胺第一受體(D1),多巴胺第二受體(D2)和多巴胺第四受體(D4),五羥色胺1A(5-HT1A)和五羥色胺2A(5-HT2A)受體以及離子通道型谷氨酸N-甲基-D-天冬氨酸受體(NMDA)受體等,而這些變化模式卻未在成年大鼠的實驗中觀察到。以上研究結(jié)果表明,青少年時期是中樞神經(jīng)系統(tǒng)發(fā)育和行為發(fā)展的關(guān)鍵時期,所以闡明抗精神病藥物對兒童、青少年患者的治療反應(yīng)及副作用產(chǎn)生的影響具有重要的臨床意義。過去的研究較多地觀察了藥物的急性作用機制,而缺乏對長期作用機制的研究存在。在臨床以及前臨床研究方面,有研究發(fā)現(xiàn)長期應(yīng)用抗精神病藥后會導致個體對藥物敏感性的增強或減弱,即長期應(yīng)用抗精神病藥使得藥物對精神癥狀的抑制作用逐漸增強,稱之為抗精神病藥敏化。相反,一些患者在幾年的長期服藥后,表現(xiàn)出耐受樣現(xiàn)象,即患者需要增加抗精神病藥物劑量才能維持一定的抑制精神癥狀的效果,表明了抗精神病藥的長期應(yīng)用的效果會逐漸下降,我們稱之為抗精神病藥耐受。動物研究也發(fā)現(xiàn)了抗精神病藥引起的敏化和耐受。然而,目前研究對抗精神病藥物敏化和耐受的神經(jīng)生物學機制和心理行為并不清楚。近些年來,本實驗室集中關(guān)注了抗精神病藥長期應(yīng)用引起的藥物敏化和耐受的行為學特征及神經(jīng)生物學機制。本研究檢查了單次氟哌啶醇(HAL),氯氮平(CLZ)和兩次奧氮平(OLZ)的處理是否會導致青年大鼠行為藥理學效應(yīng)產(chǎn)生時間依賴性變化,以及這種變化是否因性別而異。選取青年Sprague-Dawley大鼠(40天),首先單次注射氟哌啶醇(0.05和0.1mg/kg,sc),氯氮平(10和20mg/kg,sc),兩次注射奧氮平(1和2mg/kg,sc)或溶媒(VEH),在條件躲避反應(yīng)(CAR)模型或PCP(苯環(huán)己哌啶)(3.20mg/kg,sc)誘導的自主運動增多模型中測試評估其抗精神病樣行為效應(yīng)。一周或三周后,用同種藥物(HAL 0.03mg/kg,CLZ 5mg/kg,OLZ 0.5 mg/kg,sc)challenge,并對大鼠躲避反應(yīng)次數(shù)和PCP(苯環(huán)己哌啶)誘導的運動增多次數(shù)進行評估。與以前的報道一致,單次HAL,CLZ和兩次OLZ的處理抑制了條件躲避反應(yīng)次數(shù)和PCP誘導的運動增多。在表達(challenge)階段,先前用氟哌啶醇和奧氮平處理的大鼠表現(xiàn)出精神病樣行為抑制作用增強效應(yīng)(敏化),而用氯氮平處理的大鼠則表現(xiàn)出減弱的抑制作用(耐受)。值得注意的是,當比較敏化和耐受效應(yīng)的大小時,PCP模型中,發(fā)現(xiàn)氟哌啶醇敏化效應(yīng)在3周時間點顯著高于1周時間點,在雌性大鼠中尤為明顯,在條件躲避反應(yīng)模型中氯氮平耐受效應(yīng)在兩個性別中均顯示時間依賴性變化,兩種模型下的奧氮平敏化效應(yīng)沒有顯著的時間依賴性變化�？傮w來說,在某些條件下,抗精神病藥物會表現(xiàn)出時間依賴性的敏化和耐受效應(yīng),且雌性似乎更為敏感。個體(例如雌性與雄性)和環(huán)境(例如特定的行為學模型)因素以及許多藥理學(例如特定藥物,藥物劑量)因素都會對抗精神病藥所致敏化和耐受效應(yīng)的強度起調(diào)節(jié)作用。目的:在PCP誘導的運動增多模型和條件躲避反應(yīng)模型(CAR)中研究分別給予青年大鼠一次氟哌啶醇,氯氮平和兩次奧氮平處理后,青年大鼠在一周和三周后再次接觸到原有藥物時的行為反應(yīng)變化以及雌性大鼠和雄性大鼠之間的反應(yīng)差異。方法:PCPMODEL:青年SD大鼠(PND34)按分組接受一次HAL(0.05或0.1mg/kg)或者VEH處理,處理后立即將其放入觀察箱中監(jiān)測大鼠的自發(fā)性活動,30 min后每只大鼠接受一次PCP(3.2 mg/kg,sc)處理后立即將大鼠放回觀察箱中繼續(xù)監(jiān)測60 min,全程一共監(jiān)測大鼠自發(fā)性活動90min。給藥后,根據(jù)分組再將每組細分為兩個亞組,一周組和三周組。大鼠在動物房不作任何處理安靜地飼養(yǎng)6天。6天后(PND 40)將一周組大鼠放入觀察箱中適應(yīng)30 min,不給予任何藥物處理。次日(PND 41),根據(jù)實驗設(shè)計安排,一周組所有大鼠接受一次原有藥物記憶的challenge測試,自發(fā)性活動的監(jiān)測范式與給藥當天的范式相同,全程仍為90 min。從給藥當天計算21天后(PND 54),三周組大鼠不接受任何藥物處理,適應(yīng)自發(fā)性活動監(jiān)測儀器30min。次日(PND55),根據(jù)實驗設(shè)計安排,三周組所有大鼠接受一次原有藥物記憶的challenge測試,自發(fā)性活動監(jiān)測范式與給藥當天的范式相同,時程仍為90 min。奧氮平組因為是給予兩次奧氮平處理,所以在PND 34和PND 37時各給予一次奧氮平處理。CARmodel:青年SD大鼠(PND 33-39)接受7天訓練(CS-US),次日(PND40)按分組接受一次抗精神病藥CLZ(20.0mg/kg)或者VEH處理1 h后放入條件躲避反射行為監(jiān)測儀器中測試(CS-only)。給藥后,根據(jù)分組分為兩個亞組,一周組和三周組,一周組大鼠在動物房不被打擾地飼養(yǎng)5天后在不接受任何藥物處理的情況下連續(xù)適應(yīng)測試儀器兩天(PND 45-46 CS-only and CS-US)。次日(PND 47),根據(jù)分組設(shè)計安排,一周組大鼠接受原有藥物記憶的challenge測試,實驗流程及程序選擇與給藥當天相同。三周組則安靜地飼養(yǎng)三周,三周后(PND 59-60)三周組大鼠在不接受任何藥物處理的情況下連續(xù)適應(yīng)測試儀器兩天。次日(PND 61),根據(jù)分組設(shè)計安排,大鼠接受原有藥物記憶的challenge測試,實驗流程以及程序選擇與給藥當天的相同。奧氮平組因為是給予兩次奧氮平處理,所以在PND 37和PND 40時各給予一次奧氮平處理。結(jié)果:HAL組:1)一次給予抗精神病藥物氟哌啶醇處理后抑制了PCP誘導的青年大鼠自主活動增多的效應(yīng)。2)在一周組challenge測試中,原先接受過HAL的大鼠與未接受過HAL處理的大鼠相比,自發(fā)性活動次數(shù)明顯減少。3)在三周組的challenge測試中,原先接受過HAL的大鼠與未接受過HAL處理的大鼠相比,自發(fā)性活動次數(shù)明顯減少。4)三周組大鼠challenge時表現(xiàn)出相較于一周組大鼠challenge測試時更低的自發(fā)性活動次數(shù),這種現(xiàn)象在雌性組更為明顯。CLZ組:1)單次數(shù)給予抗精神病藥物氯氮平處理后抑制了PCP誘導的青年大鼠運動增多的效應(yīng)和降低了躲避次數(shù)。2)在一周組的challenge測試中,原先接受過CLZ的大鼠與未接受過CLZ處理的大鼠相比,自發(fā)性活動次數(shù)和躲避次數(shù)增多。3)在三周組的challenge測試中,原先接受過CLZ的大鼠與未接受過CLZ處理的大鼠相比,自發(fā)性活動次數(shù)和躲避次數(shù)增多。4)雄性三周組challenge時表現(xiàn)出相比一周組challenge時更少的躲避次數(shù),但雌性組卻表現(xiàn)出更多的躲避次數(shù)。OLZ組:1)兩次給予抗精神分裂藥物奧氮平處理后抑制了PCP誘導的青年大鼠自發(fā)運動增多以及顯著減少躲避次數(shù)。2)一周組challenge測試中,原先接受過OLZ的大鼠與未接受過OLZ處理的大鼠相比,自發(fā)性運動次數(shù)明顯降低且躲避反應(yīng)次數(shù)減少。3)三周組challenge測試中,原先接受過OLZ的大鼠與未接受過OLZ處理的大鼠相比,自發(fā)性運動次數(shù)明顯降低且躲避反應(yīng)次數(shù)減少。4)三周組challenge測試時表現(xiàn)出比一周組challenge測試時更多的自發(fā)性活動,且這種現(xiàn)象在雌性組更明顯。結(jié)論:一次給予抗精神病藥物氟哌啶醇即表現(xiàn)出顯著抑制PCP誘導的自發(fā)性活動增多的效應(yīng)。此效應(yīng)同樣能在一次氯氮平和兩次奧氮平處理后發(fā)現(xiàn)。青年大鼠在接受過抗精神病藥物的處理的一周和三周后再次暴露于HAL時,仍然表現(xiàn)出抑制PCP誘導的運動增加的效應(yīng),即表現(xiàn)出對藥物的敏化記憶效應(yīng)。且這種敏化效應(yīng)具有時間依賴性,時間越長,敏感性越高,這種現(xiàn)象在雌性組表現(xiàn)明顯。OLZ所誘導的敏化效應(yīng)具有時間依賴性,時間越長,敏感性越低,且這種現(xiàn)象在雌性組表現(xiàn)明顯。CLZ誘導的耐受效應(yīng)具有時間依賴性,在雄性組表現(xiàn)出隨時間增長而減弱的趨勢,但雌性組表現(xiàn)出隨時間增長而增強的趨勢。綜上所述,本文創(chuàng)新之處:1.發(fā)現(xiàn)有限次數(shù)的抗精神病藥物處理能誘導產(chǎn)生敏化或耐受效應(yīng),且這種敏化或耐受效應(yīng)具有時間依賴性。2.為臨床青少年精神病患者治療提供了實驗室數(shù)據(jù)。
[Abstract]:Schizophrenia is a group of mental disorders with many obstacles, such as perception, emotion, behavior, thinking, and so on. It is characterized by the distortion of reality, accompanied by hallucinations and delusions, and the gradual deterioration of the language function of thinking. It is one of the more common central nervous system diseases that cause the enormous economic burden of individuals and society. In recent years, in children People who use antipsychotic drugs have increased year by year, and a study in the United States showed that from 1993 to 2002, the number of people less than 20 years old increased by about 6 times from.2004 to 2005, and the proportion of antipsychotics used in children and adolescents increased from 1996 to 1997 years from 7% to 2005. As long as 15%, more than 90% of them are atypical antipsychotics. Currently, the study of children and adolescents with antipsychotic drugs is mostly focused on the observation of drug effects, adverse reactions, and the lack of the effects of antipsychotic drugs on the central nervous system in this age group and behavioral changes. Research. Studies have shown that individuals at puberty may be more sensitive to psychotropic drugs because this period is an important stage of the development of the central nervous system. Previous clinical studies found that the prefrontal cortex, the striatum, the hippocampus, and other synaptic connections and receptor density, dopamine, and the five serotonin system were experienced in the period. The drug intervention in this period can change the structure and function of the brain, and this change is usually persistent, not only affects the brain and behavior changes in children and adolescents, but also affects the individual's response to the drug. Animal experiments also found that the antipsychotics of puberty rats were also found. The intervention could change the expression of many nerve receptors in the rat brain, including the dopamine first receptor (D1), dopamine second receptor (D2) and dopamine fourth receptor (D4), five hydroxytryptamine 1A (5-HT1A) and five hydroxytryptamine 2A (5-HT2A) receptor, and ion channel glutamic acid N- methyl -D- aspartate receptor (NMDA) receptor and so on. It is not observed in adult rats' experiments. These findings suggest that adolescence is a critical period for central nervous system development and behavioral development, so it is important to clarify the effects of antipsychotic drugs on the response and side effects of children and adolescents. In clinical and pre clinical studies, a long-term application of antipsychotic drugs can lead to the enhancement or weakening of drug sensitivity. Anti psychotic drug sensitization. On the contrary, some patients show tolerance after a long period of medication, that is, the patient needs to increase the dose of antipsychotic drugs to maintain a certain effect on the inhibition of mental symptoms, indicating that the effect of the long-term application of antipsychotic drugs will gradually decline, we call it antipsychotic tolerance. Animal research The sensitization and tolerance caused by antipsychotics have also been found. However, the neurobiological mechanisms and psychological behaviours of antipsychotic sensitization and tolerance are not clear. In recent years, the laboratory has focused on the behavioral characteristics of drug sensitization and tolerance induced by the long-term application of antipsychotics and the neurobiological machine. This study examined whether the treatment of single dose haloperidol (HAL), clozapine (CLZ) and two olanzapine (OLZ) could lead to a time-dependent change in behavioral pharmacological effects of young rats, and whether this change was dependent on sex. Young Sprague-Dawley rats were selected (40 days), and the first single injection of haloperidol (0.05 and 0.1mg/kg, SC), Clozapine (10 and 20mg/kg, SC), two injections of olanzapine (1 and 2mg/kg, SC) or solvent (VEH), in the conditioned avoidance response (CAR) model or the PCP (3.20mg/kg, SC) induced autonomic exercise model to evaluate its antipsychotic behavior effects. A week or three weeks later, the same drug (HAL 0.03mg/kg, CLZ 0.5, 0.5) SC) challenge, and evaluation of the number of times of avoidance response and the number of times induced by PCP (bipiperidine). Consistent with previous reports, the treatment of single HAL, CLZ and two OLZ inhibits the number of avoidance responses and the increase of PCP induced movement. At the expression (challenge) stage, the large number of haloperidol and olanzapine was previously treated Rats showed an enhanced effect of psychosis like behavioral inhibition (sensitization), while the rats treated with clozapine showed a weakened inhibitory effect (tolerance). It is worth noting that, in the PCP model, the sensitization effect of haloperidol should be significantly higher than 1 weeks at 3 weeks, and in female rats. It was particularly evident that the clozapine tolerance in the conditional avoidance response model showed time dependent changes in two sexes, and the olanzapine sensitization effect under the two models had no significant time dependent changes. Females seem more sensitive. Individuals (such as female and male) and environment (such as specific behavioral model) factors and many pharmacological factors (such as specific drugs, drug dose) factors regulate the intensity of sensitization and tolerance induced by psychotic drugs. In the model (CAR), the young rats were treated with haloperidol, clozapine and two olanzapine respectively. The behavioral responses of young rats in one and three weeks after the first and three weeks were changed and the difference between the female rats and the male rats. Methods: PCPMODEL: young SD rats (PND34) received a HA in groups. L (0.05 or 0.1mg/kg) or VEH treatment, immediately after the treatment was put into the observation box to monitor the spontaneous activity of the rat. After 30 min, each rat received a PCP (3.2 mg/kg, SC) treatment immediately after the rats were placed back in the observation box and continued to monitor the 60 min. The rats were divided into two subgroups, one week group and three week group. The rats were kept in the animal room without any treatment and kept quiet for 6 days.6 days (PND 40). The rats of one week group were put into the observation box for 30 min, and no drug treatment was given. The next day (PND 41), according to the experimental design, all rats in a week group received a challenge test of original drug memory. The monitoring paradigm of spontaneous activity was the same as that of the day of drug delivery. The whole course was still 90 min. from the day of Administration for 21 days (PND 54). The rats in the three week group did not accept any drug treatment, adapted to the spontaneous activity monitoring instrument 30min. the next day (PND55). According to the experimental design arrangement, all rats in the three week group received the original challe of the original drug memory. Nge test, the spontaneous activity monitoring paradigm was the same as the normal paradigm for the day, and the time course was still 90 min. olanzapine because it was given two olanzapine treatments, so the.CARmodel: young SD rats were treated with olanzapine at PND 34 and PND 37 (PND 33-39) for 7 day training (CS-US), and the next day (PND40) received an antipsychotic group according to the group. After the drug CLZ (20.0mg/kg) or VEH treatment 1 h was put into the conditional avoidance behavior monitoring instrument (CS-only). After the administration, the drug was divided into two subgroups, one week group and three week group, and one week group rats were kept in the animal room for 5 days without any drug treatment for two days (PND 45-46). CS-only and CS-US). The following day (PND 47), according to the group design arrangement, the rats of one week group received the challenge test of the original drug memory, the experiment flow and the program selection were the same as the day of administration. The three week group was kept quietly for three weeks, and the rats in the three week group after three weeks (PND 59-60) were continuously adapted to the test instrument without any drug treatment. The next day (PND 61), the following day (PND 61), according to the group design arrangement, the rat accepted the challenge test of the original drug memory, the experimental process and the selection of the program were the same as the day of the administration. The olanzapine group was given two olanzapine treatment, so the olanzapine treatment was given at the time of PND 37 and PND 40. Results: HAL group: 1) gave the anti spirit once. The effect of haloperidol treatment inhibited the effect of PCP induced increase of autonomic activity in young rats induced by haloperidol. In one week group of challenge tests, the number of spontaneous activity decreased significantly compared with that of the rats who had not received the HAL treatment in the one week group of challenge tests. In the challenge test of the three week group, the old rats who had previously received HAL were not accepted. Compared with the HAL treated rats, the number of spontaneous activity decreased significantly in the three week group, and the number of spontaneous activities in the three week group was lower than that in the one week group of rats. This phenomenon was more obvious in the female group than in the female group of.CLZ: 1) the single frequency of the antiseminal antipsychotic drug clozapine treatment inhibited the PCP induced green. In the one week group of challenge tests, the number of spontaneous activities and the number of evading times increased by.3 in the challenge test of the one week group and in the three week group of challenge tests, in the three week group, the rats who had previously received CLZ and had not received CLZ treatment. In comparison, the number of spontaneous activities and the number of avoidance times increased.4) the male three weeks group showed less dodge times compared with the one week group challenge, but the female group showed more avoidance times.OLZ group: 1) the two times of the antipsychotic olanzapine treatment inhibited the increase of the spontaneous movement of the young rats induced by PCP. In the one week group of challenge tests, the rats who had previously received OLZ had significantly decreased the number of spontaneous movements and reduced the number of avoidance responses to.3 compared to those who had not been treated with OLZ. In the three week group of challenge tests, the spontaneous movement of the old rats who had previously received OLZ was compared to those who had not received the OLZ treatment. The number of times significantly decreased and the number of avoidance responses decreased.4) three weeks of challenge test showed more spontaneous activity than the one week group challenge test, and this phenomenon was more obvious in the female group. Conclusion: one dose of antipsychotic drug haloperidol showed an effect of significantly inhibiting the increase of spontaneous activity induced by PCP. The same can be found after clozapine and two olanzapine. Young rats were exposed to HAL once and three weeks after the treatment of antipsychotic drugs, still showing the effect of inhibiting the increase of PCP induced movement, that is, the sensitized memory effect on the drug. The longer the time, the higher the sensitivity, the sensitization effect induced by.OLZ in the female group has time dependence, the longer the time, the lower the sensitivity, and this phenomenon shows the time dependent effect of.CLZ induced tolerance in the female group, and in the male group, the tendency to weaken with time increases, but the female group has a tendency to decrease with time. In summary, this article is innovative: 1. it is found that a limited number of antipsychotic drugs can induce sensitization or tolerance effects, and this sensitization or tolerance effect has time dependent.2. for the treatment of clinical adolescent psychosis.
【學位授予單位】：南京中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R965

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