抗精神病药物诱导药物敏化和耐受效应在青年大鼠中的时间依赖性研究

发布时间：2018-05-19 06:49

本文选题：条件躲避反射模型 + PCP模型　；参考：《南京中医药大学》2017年硕士论文

【摘要】：精神分裂症是一组具有感知,情感,行为,思维等多方面障碍的精神疾病。该病以对现实的扭曲,伴随幻觉和妄想以及思维语言功能的逐步恶化为特征,是造成个人和社会巨大经济负担的较常见的中枢神经系统疾病之一。近些年来,在儿童和青少年人群中使用抗精神病药物的患者逐年增多,美国一项研究显示,仅在1993至2002年间,使用抗精神病药物的人群中年龄小于等于20岁的人次增加了约6倍。2004至2005年间,儿童和青少年使用抗精神病药物的比例由1996至1997年间的7%增长至15%,其中90%以上是非典型抗精神病药物。目前,关于接受抗精神病药物治疗的儿童和青少年患者的研究多集中在观察药物疗效,不良反应等方面,缺乏关于抗精神病药物对此年龄阶段的患者中枢神经系统的影响以及行为学上改变的研究。研究表明,处于青春期的个体对于精神类药物的反应可能更加敏感,因为该时期是中枢神经系统发育的重要阶段。前临床研究发现该时期前额叶皮层,纹状体,海马等部位突触连接和受体密度,多巴胺以及五羟色胺系统等会经历巨大的成熟过程。该时期的药物干预可以改变大脑的结构和功能,且这种改变通常是持久的,不仅影响儿童和青少年患者大脑和行为的改变,同样会影响个体成年后对药物的反应。动物实验研究结果也发现:给予青春期的大鼠抗精神病药物干预,会改变大鼠脑内诸多神经受体的表达,包括多巴胺第一受体(D1),多巴胺第二受体(D2)和多巴胺第四受体(D4),五羟色胺1A(5-HT1A)和五羟色胺2A(5-HT2A)受体以及离子通道型谷氨酸N-甲基-D-天冬氨酸受体(NMDA)受体等,而这些变化模式却未在成年大鼠的实验中观察到。以上研究结果表明,青少年时期是中枢神经系统发育和行为发展的关键时期,所以阐明抗精神病药物对儿童、青少年患者的治疗反应及副作用产生的影响具有重要的临床意义。过去的研究较多地观察了药物的急性作用机制,而缺乏对长期作用机制的研究存在。在临床以及前临床研究方面,有研究发现长期应用抗精神病药后会导致个体对药物敏感性的增强或减弱,即长期应用抗精神病药使得药物对精神症状的抑制作用逐渐增强,称之为抗精神病药敏化。相反,一些患者在几年的长期服药后,表现出耐受样现象,即患者需要增加抗精神病药物剂量才能维持一定的抑制精神症状的效果,表明了抗精神病药的长期应用的效果会逐渐下降,我们称之为抗精神病药耐受。动物研究也发现了抗精神病药引起的敏化和耐受。然而,目前研究对抗精神病药物敏化和耐受的神经生物学机制和心理行为并不清楚。近些年来,本实验室集中关注了抗精神病药长期应用引起的药物敏化和耐受的行为学特征及神经生物学机制。本研究检查了单次氟哌啶醇(HAL),氯氮平(CLZ)和两次奥氮平(OLZ)的处理是否会导致青年大鼠行为药理学效应产生时间依赖性变化,以及这种变化是否因性别而异。选取青年Sprague-Dawley大鼠(40天),首先单次注射氟哌啶醇(0.05和0.1mg/kg,sc),氯氮平(10和20mg/kg,sc),两次注射奥氮平(1和2mg/kg,sc)或溶媒(VEH),在条件躲避反应(CAR)模型或PCP(苯环己哌啶)(3.20mg/kg,sc)诱导的自主运动增多模型中测试评估其抗精神病样行为效应。一周或三周后,用同种药物(HAL 0.03mg/kg,CLZ 5mg/kg,OLZ 0.5 mg/kg,sc)challenge,并对大鼠躲避反应次数和PCP(苯环己哌啶)诱导的运动增多次数进行评估。与以前的报道一致,单次HAL,CLZ和两次OLZ的处理抑制了条件躲避反应次数和PCP诱导的运动增多。在表达(challenge)阶段,先前用氟哌啶醇和奥氮平处理的大鼠表现出精神病样行为抑制作用增强效应(敏化),而用氯氮平处理的大鼠则表现出减弱的抑制作用(耐受)。值得注意的是,当比较敏化和耐受效应的大小时,PCP模型中,发现氟哌啶醇敏化效应在3周时间点显着高于1周时间点,在雌性大鼠中尤为明显,在条件躲避反应模型中氯氮平耐受效应在两个性别中均显示时间依赖性变化,两种模型下的奥氮平敏化效应没有显著的时间依赖性变化。总体来说,在某些条件下,抗精神病药物会表现出时间依赖性的敏化和耐受效应,且雌性似乎更为敏感。个体(例如雌性与雄性)和环境(例如特定的行为学模型)因素以及许多药理学(例如特定药物,药物剂量)因素都会对抗精神病药所致敏化和耐受效应的强度起调节作用。目的:在PCP诱导的运动增多模型和条件躲避反应模型(CAR)中研究分别给予青年大鼠一次氟哌啶醇,氯氮平和两次奥氮平处理后,青年大鼠在一周和三周后再次接触到原有药物时的行为反应变化以及雌性大鼠和雄性大鼠之间的反应差异。方法:PCPMODEL:青年SD大鼠(PND34)按分组接受一次HAL(0.05或0.1mg/kg)或者VEH处理,处理后立即将其放入观察箱中监测大鼠的自发性活动,30 min后每只大鼠接受一次PCP(3.2 mg/kg,sc)处理后立即将大鼠放回观察箱中继续监测60 min,全程一共监测大鼠自发性活动90min。给药后,根据分组再将每组细分为两个亚组,一周组和三周组。大鼠在动物房不作任何处理安静地饲养6天。6天后(PND 40)将一周组大鼠放入观察箱中适应30 min,不给予任何药物处理。次日(PND 41),根据实验设计安排,一周组所有大鼠接受一次原有药物记忆的challenge测试,自发性活动的监测范式与给药当天的范式相同,全程仍为90 min。从给药当天计算21天后(PND 54),三周组大鼠不接受任何药物处理,适应自发性活动监测仪器30min。次日(PND55),根据实验设计安排,三周组所有大鼠接受一次原有药物记忆的challenge测试,自发性活动监测范式与给药当天的范式相同,时程仍为90 min。奥氮平组因为是给予两次奥氮平处理,所以在PND 34和PND 37时各给予一次奥氮平处理。CARmodel:青年SD大鼠(PND 33-39)接受7天训练(CS-US),次日(PND40)按分组接受一次抗精神病药CLZ(20.0mg/kg)或者VEH处理1 h后放入条件躲避反射行为监测仪器中测试(CS-only)。给药后,根据分组分为两个亚组,一周组和三周组,一周组大鼠在动物房不被打扰地饲养5天后在不接受任何药物处理的情况下连续适应测试仪器两天(PND 45-46 CS-only and CS-US)。次日(PND 47),根据分组设计安排,一周组大鼠接受原有药物记忆的challenge测试,实验流程及程序选择与给药当天相同。三周组则安静地饲养三周,三周后(PND 59-60)三周组大鼠在不接受任何药物处理的情况下连续适应测试仪器两天。次日(PND 61),根据分组设计安排,大鼠接受原有药物记忆的challenge测试,实验流程以及程序选择与给药当天的相同。奥氮平组因为是给予两次奥氮平处理,所以在PND 37和PND 40时各给予一次奥氮平处理。结果:HAL组:1)一次给予抗精神病药物氟哌啶醇处理后抑制了PCP诱导的青年大鼠自主活动增多的效应。2)在一周组challenge测试中,原先接受过HAL的大鼠与未接受过HAL处理的大鼠相比,自发性活动次数明显减少。3)在三周组的challenge测试中,原先接受过HAL的大鼠与未接受过HAL处理的大鼠相比,自发性活动次数明显减少。4)三周组大鼠challenge时表现出相较于一周组大鼠challenge测试时更低的自发性活动次数,这种现象在雌性组更为明显。CLZ组:1)单次数给予抗精神病药物氯氮平处理后抑制了PCP诱导的青年大鼠运动增多的效应和降低了躲避次数。2)在一周组的challenge测试中,原先接受过CLZ的大鼠与未接受过CLZ处理的大鼠相比,自发性活动次数和躲避次数增多。3)在三周组的challenge测试中,原先接受过CLZ的大鼠与未接受过CLZ处理的大鼠相比,自发性活动次数和躲避次数增多。4)雄性三周组challenge时表现出相比一周组challenge时更少的躲避次数,但雌性组却表现出更多的躲避次数。OLZ组:1)两次给予抗精神分裂药物奥氮平处理后抑制了PCP诱导的青年大鼠自发运动增多以及显著减少躲避次数。2)一周组challenge测试中,原先接受过OLZ的大鼠与未接受过OLZ处理的大鼠相比,自发性运动次数明显降低且躲避反应次数减少。3)三周组challenge测试中,原先接受过OLZ的大鼠与未接受过OLZ处理的大鼠相比,自发性运动次数明显降低且躲避反应次数减少。4)三周组challenge测试时表现出比一周组challenge测试时更多的自发性活动,且这种现象在雌性组更明显。结论:一次给予抗精神病药物氟哌啶醇即表现出显著抑制PCP诱导的自发性活动增多的效应。此效应同样能在一次氯氮平和两次奥氮平处理后发现。青年大鼠在接受过抗精神病药物的处理的一周和三周后再次暴露于HAL时,仍然表现出抑制PCP诱导的运动增加的效应,即表现出对药物的敏化记忆效应。且这种敏化效应具有时间依赖性,时间越长,敏感性越高,这种现象在雌性组表现明显。OLZ所诱导的敏化效应具有时间依赖性,时间越长,敏感性越低,且这种现象在雌性组表现明显。CLZ诱导的耐受效应具有时间依赖性,在雄性组表现出随时间增长而减弱的趋势,但雌性组表现出随时间增长而增强的趋势。综上所述,本文创新之处:1.发现有限次数的抗精神病药物处理能诱导产生敏化或耐受效应,且这种敏化或耐受效应具有时间依赖性。2.为临床青少年精神病患者治疗提供了实验室数据。
[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.
【学位授予单位】：南京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R965

【相似文献】