多次给药精神分裂症行为模型评价及应用
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摘要
精神分裂症是一种常见的病因尚未完全阐明的精神疾病。多起病于青壮年，常缓慢起病，具有思维、情感、行为等多方面障碍，精神活动与环境不协调。通常无意识及智能障碍。病程多迁延，呈反复加重或恶化。精神分裂症的症状分为阳性和阴性症状，前者包括幻觉、妄想和思维障碍等，后者主要包括社交障碍、兴趣缺失及情感障碍。另外精神分裂症患者还伴有认知功能缺损、学习记忆障碍和工作记忆障碍等。
应用抗精神分裂症药物是目前治疗精神分裂症的主要手段。第一代抗精神分裂症药物是以氟哌啶醇为代表的经典型抗精神分裂症药物，其通过阻断多巴胺D2受体起到治疗作用。经典型抗精神分裂症药物能有效控制精神分裂症阳性症状，但对阴性症状的疗效甚差，并且长期用药会产生严重的副反应，如：锥体外系症状、性功能障碍、直立性低血压、神经内分泌紊乱及镇静，这些都限制了经典型抗精神分裂症药物的使用。第二代抗精神分裂症药物是以氯氮平、奥氮平为代表的非经典型抗精神分裂症药物。这类药物和多巴胺D2受体的结合率相对较低，但和其他受体的结合率相对较高，如：5-HT_(2A)、5-HT_(1A)、α1-肾上腺素、α2-肾上腺素受体。与经典型抗精神分裂症药物相比，非经典型抗精神分裂症药物不仅可以有效控制精神分裂症阳性症状，同时减少了发生锥体外系副反应的可能性。然而，第二代抗精神分裂症药物能产生其他的副反应，如：体重增加、二型糖尿病、高血糖症及脂质代谢障碍。另外，超过30%的精神分裂症患者对任何药物治疗均不敏感，病情持续活跃。目前抗精神分裂症药物对阴性症状疗效极其有限，同时可以产生众多副作用，因此当前精神分裂症的药物治疗现状并不乐观，迫切需要开发新的药物来缓解精神分裂症患者的阴性症状及认知障碍，以此来提高精神分裂症患者的生活质量。
动物模型在研究人类疾病及开发新药方面起着非常重要的作用，而目前有关精神分裂症的病因学及病理生理学尚未阐明。另外，这类疾病的许多症状很难在啮齿类动物上直接进行检测，如：妄想、散发性思维等，因此，建立能适当地反映精神分裂症这样具有复杂神经精神异常的动物模型非常困难。
应用动物行为学模型是研究精神分裂症及开发、筛选新型抗精神分裂症药物的最主要手段。在我们可以检测抗精神分裂症药物在患者上的作用前，我们必须首先研究药物在动物行为学上的作用。一个理想的精神分裂症动物模型的重要因素是其对于当前及未来的治疗有着较高的预测效度。然而，目前没有一种理想的动物模型能模拟所有精神分裂症患者的症状，每一种模型只能模拟精神分裂症的某个方面的特点。因此精神分裂症治疗手段的预测型模型仅仅反应抗精神分裂症药物的局限的一个方面的作用，并且在此情况下，研究者通常只是检测急性给予抗精神分裂症药物对于多巴胺或谷氨酸受体介导的行为异常的作用。还未有多次给药动物行为模型的相关报道及初步行为机制探讨。而临床上精神分裂症患者是长期服药且症状长期存在。所以迫切需要开发一些改良的精神分裂症模型来更好的反应药物对精神分裂症的治疗作用。
ATP敏感性钾通道（ATP-sensitive potassium channel，K-ATP通道）是一类耦联细胞代谢和电活动、以细胞内的ATP/ADP水平为门控因素、非电压依赖性的特殊钾离子通道。近年来，包括本实验室在内的研究表明K-ATP通道特别是线粒体K-ATP通道（mitochondrial ATP-sensitive potassium channel，mitoK-ATP通道）不仅是急性缺血缺氧、氧化应激等病理因素损伤时机体的重要内源性保护机制，而且与神经退行性疾病（neurodegenerative diseases），包括PD，阿尔茨海默病（Alzherimer’s disease, AD）相关。
新型K-ATP通道开放剂埃他卡林（Iptakalim，IPT）是我国学者自行设计、合成的脂肪仲胺类小分子化合物，最初开发用于治疗高血压，它通过开放心血管KATP通道起到抗高血压作用。后期研究表明埃他卡林可以穿透血脑屏障并作用于神经元细胞或胶质细胞膜上KATP通道及线粒体KATP通道，使得在整体动物模型上研究、评价K-ATP通道开放剂的神经系统作用成为可能。
本实验室前期研究显示盐酸埃他卡林有望用于治疗精神分裂症，有望改善精神分裂症患者的阴性症状及认知功能障碍。首先：在体或离体实验已证实盐酸埃他卡林可以抑制多巴胺的过度释放。研究表明埃他卡林可以显著抑制鱼藤酮或GBR-12909诱导PC12细胞释放多巴胺，在体微透析研究亦表明埃他卡林可以抑制MPP+或尼古丁诱导的多巴胺释放。更加让我们感兴趣的是：在单侧6-OHDA造模的PD大鼠中，埃他卡林可以显著降低健侧细胞外多巴胺水平，而显著升高损毁侧细胞外多巴胺水平，这种特征与多巴胺的部分激动剂，如：阿立哌唑，非常相似。其次，研究证实埃他卡林可以通过抗凋亡，抗坏死起到神经保护作用，这些均与埃他卡林抑制谷氨酸释放，调节谷氨酸能受体相关。另外，在动物行为学研究中发现，埃他卡林可以逆转氟哌啶醇诱导的肌僵直和低运动能力。用埃他卡林或二氮嗪（一种线粒体ATP敏感性钾通道开放剂）对动物进行预保护可以阻止鱼藤酮诱导的肌僵直，并且可以减少纹状体多巴胺含量。以上这些发现提示埃他卡林有可能可以在不同脑区对多巴胺含量进行调节，使之趋于正常水平，从而起到多巴胺稳定剂的作用。KATP通道大量存在于黑质、腹侧被盖区、前额皮质、及海马，这些区域对于神经递质如：谷氨酸，多巴胺，GABA的调节有着重要作用，并且这些区域与精神分裂症的病理生理严密相关。埃他卡林已被证实可以通过开放KATP通道而起到独特的抗高血压效果，精神分裂症患者往往伴有高血压，从而埃他卡林的这种抗高血压效果非常具有吸引力。另外，已有文献基于多巴胺受体可以调节KATP通道开放的事实作出KATP通道开放剂有望治疗精神分裂症的假设。事实上，已有研究临床研究证实，二氮嗪联合氟哌啶醇用药可以显著提高临床疗效，二氮嗪可以强化氟哌啶醇对阳性症状的控制作用，并可改善精神分裂症患者的一般精神症状。
前期研究结果提示IPT是富有前景的靶向于K-ATP通道的新型抗精神分裂症药物。然而，目前学术界尚未见K-ATP通道开放剂对精神分裂症的治疗作用的报道。
多次给药动物行为学模型是否与急性模型一致？多次给药动物模型的行为学机制是什么？K-ATP通道开放剂是否对精神分裂症动物模型有治疗作用？K-ATP通道是否是治疗精神分裂症的潜在靶点？这些科学问题的阐明，不仅开拓了神经精神的新领域，也将为发展理想的神经保护剂提供新的靶标。因此，本文工作第一部分首先应用建立多种多次给药大鼠精神分裂症行为学模型，系统研究了多次给药与急性给药模型的差异。第二部分在发现多次给药模型更优越的基础上，研究多次给药模型的相关行为学机制；第三部分研究K-ATP通道开放剂IPT在多次给药动物行为学模型中对精神分裂症的实验治疗学作用。
第一部分多次给药精神分裂症行为模型的建立及意义
目的：建立多次给药精神分裂症行为学模型，研究、阐明多次给药精神分裂症模型与急性给药模型在进行抗精神分裂症药物筛选中的差异及意义。
方法：建立多次给药快速运动大鼠模型方法：给药前两天开始适应测试环境及测试箱，自第三天起，连续5天先给予SD大鼠CLZ（5.0、10.0、20.0mg·kg~(-1)·day~(-1), s.c.）、HAL（0.01、0.05、0.10 mg·kg~(-1)·day~(-1), s.c.）、RIS（0.30、0.10mg·kg~(-1)·day~(-1), s.c.）、CDP（10.0 mg·kg~(-1)·day~(-1), i.p.）、FLU（5.0、10.0 mg·kg~(-1)·day~(-1),i.p.）或生理盐水，半小时候后给予SD大鼠AMPH（1.5 mg·kg~(-1)·day~(-1), s.c.）或PCP（3.2 mg·kg~(-1)·day~(-1), s.c.）或生理盐水。于每天第一次给药后开始记录大鼠运动情况，连续记录90分钟（含给致幻药前的30分钟及致幻药后的60分钟），连续记录5天。
建立多次给药条件躲避反射模型方法：给药前两天开始适应测试环境及测试箱，自第三天起，在连续两周时间内给予SD大鼠条件躲避反射训练十次。SD大鼠被放入一个被栅栏分隔成两部分的测试箱，大鼠可以在这两部分间自由穿过。即先给予大鼠一个信号：声音信号，然后给动物一次电击，最终使SD大鼠能把这两种刺激联系起来，从而接受到信号后可以穿越到箱子的另一边以躲避电击，形成条件躲避反射。每次训练含有二十次声音信号和电击。最后连续两天能成功躲避百分之七十以上即被认为学会了条件躲避反射，即成功躲避14次的SD大鼠进入下一阶段实验。停止训练后即连续5天给予SD大鼠CLZ（5.0、10.0、20.0 mg·kg-1·day~(-1), s.c.）或HAL（0.01、0.05、0.10 mg·kg-1·day~(-1), s.c.）或生理盐水，一小时后放入条件躲避反射测试箱测试，记录大鼠条件躲避反射次数。
结果：1）急性快速运动实验中，CLZ、HAL、OLZ均剂量依赖性地抑制AMPH或PCP诱导的运动行为增强，同时急性状态下CLZ、OLZ更倾向于抑制PCP诱导的快速运动行为，而HAL更倾向于抑制AMPH诱导的快速运动行为。2）在多次给药快速运动实验中，随着给药次数的增多，CLZ、HAL、OLZ逐渐丧失对AMPH诱导的快速运动行为的抑制能力，而在PCP诱导的快速运动行为实验中，随着给药次数的增多，CLZ、HAL、OLZ对快速运动行为的抑制能力在增强，而CDP并不能显示这种能力。3）在多次给药条件躲避反射实验中，随着给药次数的增多，HAL对SD大鼠条件躲避反射的抑制能力逐渐增强，而CLZ随着给药次数的增多，逐渐丧失对大鼠条件躲避反射的抑制能力。
结论：联合急性给药和多次给药快速运动行为学模型可以区分经典型或非经典型抗精神分裂症药物，多次给药PCP诱导的快速运动行为模型可以更好地模拟临床上的给药情况。
第二部分多次给药精神分裂症行为模型的行为机制和受体机制
目的：在建立PCP多次给药快速运动行为学模型基础上，研究、阐明多次给PCP行为学模型的行为机制。在建立HAL、CLZ多次给药条件躲避反射模型基础上，研究、阐明HAL及CLZ抑制条件躲避反射的受体学机制。
方法：在多次给予PCP动物模型上首先检测不同给药史对多次PCP诱导的快速运动行为的作用：在饲养笼内连续5天给予SD大鼠CLZ（10.0mg·kg-1·day~(-1),s.c.）或HAL（0.05mg·kg-1·day~(-1), s.c.）或OLZ（2.0 mg·kg-1·day~(-1), s.c.）或生理盐水，从第6天起连续5天先给予SD大鼠CLZ（10.0mg·kg-1·day~(-1), s.c.）或HAL（0.05mg·kg-1·day~(-1), s.c.）或OLZ（2.0 mg·kg-1·day~(-1), s.c.）或生理盐水，半小时后给予SD大鼠PCP（3.2 mg·kg-1·day~(-1), s.c.），同时于第6天起每天给药后把SD大鼠放入快速运动行为测试箱进行测试，记录大鼠运动情况，连续记录90分钟（含给PCP前的30分钟及PCP后的60分钟），连续记录5天。其次检测相同给药史前提下，不同测试环境暴露史对多次PCP诱导的快速运动行为的作用：连续7天给予SD大鼠HAL（0.03mg·kg-1·day~(-1), s.c.），半小时候给予SD大鼠PCP（1.6mg·kg-1·day~(-1), s.c.），一组于给药第一天即放入测试箱测试记录，一组在饲养笼内连续给药两天，于第三天放入测试箱测试记录，另外一组在饲养笼内连续给药四天，于第五天放入测试箱测试记录。
在多次给药条件躲避反射模型上，给药前两天开始适应测试环境及测试箱，自第三天起，在连续两周时间内给予SD大鼠条件躲避反射训练十次。训练结束后连续3天给予成功获得条件躲避反射能力的大鼠QUI（1.0mg·kg-1·day~(-1), s.c.）或DO（I 2.5mg·kg-1·day~(-1), s.c.），十分钟后分别给予SD大鼠HAL（0.05mg·kg-1·day~(-1),s.c.）或CLZ（10.0mg·kg-1·day~(-1), s.c.）或OLZ（1.0mg·kg-1·day~(-1), s.c.），抗精神分裂症药物给药半小时后放入条件躲避反射测试箱测试记录。
结果：1）有抗精神分裂症药物给药史的大鼠并不能在首次测试时达到最强抑制效果。2）在相同给药史情况下，暴露于测试环境下的次数越多，抑制快速运动行为的能力更强。3）HAL抑制条件躲避反射的能力可以被QUI所逆转，而CLZ抑制条件躲避反射的能力可以被DOI所逆转。
结论：抗精神分裂症药物对于多次PCP诱导的快速运动行为的逐渐增强效应依赖于抗精神分裂症药物与PCP的相互作用，同时亦依赖于药物与环境的相互作用。HAL通过阻断D2受体发挥抑制条件射避反射作用，而CLZ通过阻断5HT2受体发挥作用。
第三部分K-ATP通道开放剂对精神分裂症的实验治疗学作用
目的：研究、阐明K-ATP通道开放剂在多种动物行为学模型中对精神分裂症的实验治疗学作用。
方法：应用快速运动行为检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对AMPH（1.5 mg·kg-1·day~(-1)，s.c.）、PCP（3.2 mg·kg-1·day~(-1)，s.c.）诱导的快速运动行为的抑制效果，应用条件躲避反射模型检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对SD大鼠条件躲避反射的抑制效果，应用PPI模型，检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对AMPH（1.5 mg·kg-1·day~(-1)，s.c.）或PCP（3.2 mg·kg-1·day~(-1)，s.c.）诱导的PPI损害的影响。应用免疫组织化学检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对精神分裂症相关脑区c-FOS表达的影响。应用肌僵直模型检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）本身对SD大鼠肌僵直的影响。
结果：1) IPT（60mg·kg-1·day~(-1)，i.p.）在急性状态下可以抑制AMPH、PCP诱导的快速运动行为，且更倾向于抑制PCP诱导的快速运动，与CLZ相一致，随着给药次数增多而丧失抑制能力。2) IPT（60mg·kg-1·day~(-1)，i.p.）在急性状态下可以抑制条件躲避反射，随着给药次数增多而丧失抑制能力，与CLZ相一致。3) IPT无法逆转AMPH或PCP诱导的PPI损害。4) IPT诱导的相关脑区c-FOS表达情况与CLZ相一致。5) IPT本身不影响肌僵直。
结论：K-ATP通道开放剂IPT在多种精神分裂症行为学模型中显示了一定的有效性，K-ATP通道有望成为抗精神分裂症药物开发的新靶点。
综上所述，本文工作的主要创新之处在于：
1.建立了多个多次给药动物行为学模型用于研究精神分裂症，揭示联合使用急性模型和多次给药模型或联合应用多巴胺类致幻剂和谷氨酸类致幻剂可以更好地研究、区分抗精神分裂症药物作用特点和类别。为筛选新的抗精神分裂症药物积累了必要的学术与实验基础。
2.阐明多次给药PCP快速运动模型的行为学机制，不仅依赖于药物和药物的相互作用，还依赖于药物和环境的相互作用。同时阐明HAL及CLZ在条件躲避反射中起抑制作用的受体学基础。为进一步机制研究提供了必要的学术基础。
3.发现K-ATP通道开放剂IPT对多种精神分裂症行为学模型有治疗作用，且与CLZ相似。研究结果为发展靶向于K-ATP通道的药物用于精神分裂症的临床治疗提供了理论依据。
Schizophrenia is an etiology unknown mental disorder. Onset of symptomstypically occurs in young adulthood, characterized by abnormalities in the thought,emotion and behavior. The symptoms of schizophrenia include positive and negativesymptoms, the positive symptoms most commonly manifests as hallucinations,disorganized thinking, and the negative symptoms most commonly manifests associal withdrawal and anhedonia. In addition, patients with schizophrenia also showcognitive impairment such as working memory and attention impairment.
Antipsychotic drugs (APDs) are the main medications used to treatschizophrenia. The first-generation APDs (typical APDs, e.g., haloperidol) areprimarily dopamine D2 receptor antagonists. They are most effective in the control ofpsychotic symptoms but have a high propensity for producing severe side effects,such as extrapyramidal symptoms (EPS), sexual dysfunction, orthostatic hypotension,neuroendocrine disturbances, and sedation, which limit the therapeutic usefulness ofAPDs and reduce the patient’s quality of life. The second-generation APDs (atypicalAPDs, clozapine, olanzapine) display a lower affinity for dopamine D2 receptors andhigher affinities for other receptors, such as 5-HT2A, 5-HT1A andα1- adrenergic and α2 - adrenergic receptors. In comparison to typicals, atypical APDs are equallyeffective against psychotic symptoms but have a reduced risk of EPS. However,atypicals can cause other unwanted side effects, such as weight gain, type II diabetes,hyperglycemia, and dyslipidemia. In addition, more than 30% of patients respondpoorly to any drug treatment and remain actively psychotic. Thus, it is it safe to saythat the current psychopharmacological treatments for schizophrenia areunsatisfactory because of their limited effectiveness on non-psychotic symptoms andthe disturbing side effects that they can cause. Consequently, there is a pressing needto develop better drugs that offer hope for the alleviation of negative symptoms andcognitive deficits in schizophrenia, to improve the quality of life of schizophrenicpatients.
Animal behavior models are extremely useful tools in researching pathogenesisand treatment of human disease. Creating adequate animal models of complexneuropsychiatric disorders such as schizophrenia represents a particularly difficultchallenge. In the case of schizophrenia, little is certain regarding the etiology orpathophysiology of the human disease. In addition, many symptoms of the disorderare difficult to measure directly in rodents.
Predictive validity for current and future therapies is one of the more desirablefeatures of an ideal animal model of schizophrenia. However, some current“predictive models”of schizophrenia treatment measure only a single dimension ofantipsychotic drug effects, often testing the effects of acute antipsychotic drugadministration on dopamine or glutamate receptor-mediated behaviors. Improvedmodels of schizophrenia will likely lead to unique advances in schizophreniatreatment.
ATP-sensitive potassium channel (K-ATP channel) is a special class ofpotassium channel, which links cell metabolic state to excitability. K-ATP channelsconsist of discrete pore-forming and regulatory subunits and are activated by adecrease in ATP/ADP ratio. Recently, it is demonstrated that K-ATP channelespecially mitochondrial K-ATP (mitoK-ATP) channel is the importantneuroprotective target, and may be the endogenous protective mechanism after ischemic, hypoxia or oxidative stress-induced injury. Moreover. K-ATP channelparticipates in the initiation and progress of Parkinson s disease (PD), Alzherimer'sdisease (AD')
Iptakalim was originally developed for the treatment of hypertension. It is anovel adenosine tnphosphate (ATP)-sensitive potassium channel activator that opensthe cardiovascular K-ATP channels and exerts an antihypertensive effect. Becauseiptakalim was later found to be able to easily pass through the blood-brain-barrier andto act on the neuronal plasma membrane and/or mitochondrial K-ATP channels, itspotential therapeutic effects ou neurological and neuropsychiatric disorders havegenerated much interest Current research focuses on the neuronal protective effectsof lptakalim on ischenic stroke. Parkinson s disease (PD) and its potential therapeuticeffect on nicotine addiction
Several lines of indirect evidence suggest lhat lptafcalim may be potentiallyuseful for schizophrenia and may offer needed efficacies on negative and cognitivesymptoms First, in vitro and in vivo experiments demonstrate that iptakalim has aninhibitory function on excess dopamine release. Iptakalim is found to significantlyreduce dopamine release induced by rotenone or GBR-I2909 in rat dopaminergicPC 12 cells and to attenuate dopamine release induced by1-methy1-4-phenylpyridinium ion (MPP(+)) or nicotine m freely moving ratsInterestingly, in the unilateral 6-hydroxydopamine (6-OHDA) lesioned rats (a modelof PD). iptakalim is shown to significantly decrease extracellular dopamine levels inthe intact side of the sratum. while increasing dopamine levels in the lesioned sideThis unique property in some ways resembles lhat of a dopamine partial agonist, suchas aripiprazole, and suggests that iptakalim may be capable of adjusting the level ofdopamine in different parts of the brain Second, iptakalim is demonstrated to possessan intrinsic neuroprotective effect against necrosis and apoptosis due to its ability tolimit glutamate release and receptor functions. Third, in animal behavioral studies.iptakalim is shown to reverse haloperidol-induced catalepsy and hypolocomotionPretreatment with iptakalim or diazoxide (a selective mitochondrial ATP-sensitivepotassium channel opener) can even prevent rotenone-induced catalepsy and the reduction of striatum dopamine contents. These fomdomgs, together with evidencereviewed above showing that lptakalim can inhibit excess dopamine release, stronglysuggest that iptakalim may function as a ""dopamine stabilizer to modulate theappropriate level of dopamine in different parts of the brain. It may increasedopamine release at the site where tbe dopamine level is low, while decreasingdopamine release at the site where the dopamine level is high. Fourth, iptakalim isshown to possess a unique antihypertensive effect via the opening of the K-AXPchannels in several animal models. This antihypertensive effect of iptakalim is anattractive feature because hypertension is common in patients with psychiatric illness.Interestingly, most antipsychotic drugs also have a similar hypotensive effect.although via quite different physiological mechanisms. Nevertheless, this similarityadds to the support for the proposition that iptakalim may possess an antipsychoticproperty. Fifth the target site of iptakalim -the K-ATP channel- is found in the neuralcircuits that are implicated in the pathophysiology of scluzophrenia. such as thesubstantia nigra, ventral tegmental area, the prefrontal cortex and hippocampus, andplays an important role in the regulation of release of neurotransmitters, such asglutamate. dopamine and GABA Finally, it has been hypothesized that the K-ATPchannel activators may be beneficial in schizophrenia based on the evidence thatdopamine receptors can modulate the K-ATP channel opening. Diazoxide theATP-sensitive potassium channel opener has been tried m the clinic as an adjunctivetreatment together with haloperidol. It potentiated the effects of haloperidol on thepositive and general psychopathological symptoms of schizophrenia as measured byPANSS.
In the present study, we first evaluated several rat behavioral models forantipsychotic activity. Then we used these newly developed models and exploredthe behavioral and receptor mechanisms underlying acute and repeated effects ofantipsychotic treatment Finally, we investigated the potential antipsychotic effect ofK-ATP channel opener EPT on preclinical scluzophrenia behavior model.
Part I Significance of the repeated antiphychotic treatmentschizophrenia model
AIM: To investigated whether repeated antipsychotic treatment could producean early-onset and progressively increased antagonistic effect on amphetamine orphencyclidineinduced hyperlocomotion and on conditioned avoidance response as away of assessing the validity of such models in capturing time course of antipsychoticaction.
METHODS: For the hyperlocomotion test, on each of the five consecutive testdays, different groups of rats (n=6–7/group) received an initial injection of eitherhaloperidol (0.01–0.10 mg/kg, sc), clozapine (5–20.0 mg/kg, sc), olanzapine (1.0mg/kg, sc), chlordiazepoxide (10.0 mg/kg, ip) or vehicle (sterile water, sc) 30 minprior to a second injection of either amphetamine (1.5 mg/kg, sc) or phencyclidine(3.2 mg/kg, sc). Motor activity was subsequently monitored for 60 min afteramphetamine or phencyclidine treatment. For the CAR test, on each of the fiveconsecutive test days, different groups of rats (n=6–7/group) received an injection ofeither haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or vehicle (sterilewater, sc). Conditioned avoidance response monitored 60 min after HAL、CLZ orVEH treatment.
RESULTS: 1) Repeated treatment of haloperidol, clozapine, or olanzapineprogressively potentiated inhibition on repeated phencyclidine-inducedhyperlocomotion and prolonged this action over the five consecutive days；2) Incontrast, antipsychotic inhibition on repeated amphetamine-induced hyperlocomotionwas gradually attenuated and shortened；3) Repeated treatment of chlordiazepoxide, abenzodiazepine anxiolytic, retained its inhibition on amphetamine-inducedhyperlocomotion, but had no effect on phencyclidine-induced one；4) Repeatedtreatment of haloperidol progressively potentiated inhibition on conditionedavoidance response; 5) In contrast, repeated treatment of clozapine progressivelyattenuated inhibition on conditioned avoidance response.
CONCLUSION: R e p eated phencyclidine-induced hyperlocomotion model repeated antipsychotic treatment regimen is capable of capturing theprogressive increase pattern of antipsychotic treatment seen in the clinic anddifferentiating antipsychotics from anxiolytics; thus it may serve as a better modelfor the investigation of the neurobiological mechanisms of action of antipsychoticdrugs and delineating the pathophysiology of schizophrenia.
Part II Mechanisms underlying repeated antiphychotictreatment schizophrenia model
AIM: To investigate the behavioral and receptor mechanisms underlying acuteand repeated effects of antipsychotic treatment.
METHODS: For different antipsychotic treatment history test: First, differentgroups of rats (n=6–7/group) received an injection of either haloperidol (0.05 mg/kg,sc), clozapine (5 mg/kg, sc), olanzapine (2.0 mg/kg, sc), or vehicle (sterile water, sc)in the homecages for daily for five consecutive days, then, on the next five test days,they were injected with either haloperidol (0.05 mg/kg, sc), clozapine (5 mg/kg, sc),olanzapine (2.0 mg/kg, sc), or vehicle (sterile water, sc) 30 min prior to a secondinjection of phencyclidine (3.2 mg/kg, sc) before being placed in the motor activitytesting boxes. Motor activity was monitored for 60 min after phencyclidine treatment.Some rats that received vehicle in the first five days received either haloperidol (0.05mg/kg, sc), clozapine (5 mg/kg, sc), olanzapine (2.0 mg/kg, sc) in the second test days.For different testing room exposure test: on each of 7 consecutive test days, differentgroups of rats (n=8/group) received an initial injection of either haloperidol (0.03mg/kg, sc), clozapine (5 mg/kg, sc), olanzapine (1.0 mg/kg, sc), or vehicle (sterilewater, sc) 30 min prior to a second injection of phencyclidine (1.6 mg/kg, sc) in theirhomecages or testing boxes. Motor activity was subsequently monitored for 60 minafter phencyclidine treatment.
For the CAR test: well-trained rats were administered with haloperidol (0.05 mg/kg,sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with eithersterile water, quinpirole (a selective dopamine D2/D3 agonist, 1.0 mg/kg, sc), and/or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT2A/2C agonist, 2.5 mg/kg,sc), and their avoidance behavior were tested over three consecutive days. After twodays drug-free retraining, the repeated treatment effect (i.e. drug memory) wasassessed in a challenge test.
RESULTSRESULTS: 1) Preexposure to the antipshchotic did not afftect the inhibition ofantipsychotic treatment on acute PCP-induced hyperlocomotion.; 2) Differentexposure times affect the inhibition effect of HAL, but not CLZ, OLZ, onPCP-induced hyperlocomotion；3) Pretreatment of quinpirole, but not DOI,attenuated the acute haloperidol-induced disruption of avoidance responding and to alesser extent, olanzapine-induced disruption；4) In contrast, pretreatment of DOI, butnot quinpirole, attenuated that of clozapine；5) On the repeated effect, pretreatmentof DOI attenuated the haloperidol drug memory, whereas pretreatment of quinpiroleattenuated olanzapine drug memory and potentiated that of clozapine.
CONCLUSION: The progressively potentiated inhibition of repeated treatmentof haloperidol, clozapine, or olanzapine on repeated phencyclidine inducedhyperlocomotion depends on the drug-drug interaction and drug-environmentinteraction. Acute haloperidol and olanzapine disrupt avoidance responding primarilyby immediately blocking dopamine D2 receptors, whereas acute clozapine exerts itsdisruptive effect primarily by blocking the 5-HT2A/2C receptors. The repeatedhaloperidol and clozapine effect may be mediated by brain changes initiated by5-HT2A/2C blockade, whereas the repeated olanzapine effect may be mediated by brainchanges initiated by D2 blockade.
Part III Effect of iptakalim in schizophrenia models
AIM: To examine the potential antipsychotic activity of iptakalim (IPT) inseveral schizophrenia animal behavioral models
METHODS: We used some preclinical animal behavioral model to investigatethe potential antipsychotic activity of IPT：1) amphetamine- andphencyclidine-induced hyperlocomotion；2) conditioned avoidance responding model; 3) amphetamine- and phencyclidine-induced prepulse inhibition deficit model; 4)Immunohistochemistry was taken for analyses of IPT induced C-fos expression inthe nucleus accumbens, medial prefrontal cortex, lateral septal nucleus, anddorsolateral striatum.
RESULTSRESULTS: 1) IPT is effective in reducing amphetamine- andphencyclidine-induced hyperlocomotion and shows a preferential effect in reducingthe PCP-induced hyperlocomotion over the amphetamine-induced one；2) acuteiptakalim treatment selectively and dose-dependently disrupts conditioned avoidanceresponding. Repeated iptakalim treatment gradually loses its inhibition on avoidanceresponding, an effect shared only by clozapine, but not by other antipsychotics tested,such as haloperidol, olanzapine and risperidone; 3) iptakalim itself does not disruptprepulse inhibition (PPI) of acoustic startle reflex or cause catalepsy. It potentiates theamphetamine-induced reduction of PPI but is ineffective in reversing thephencyclidine-induced disruption; 4) iptakalim and clozapine, but not haloperidol,preferentially induces Fos-like immunoreactivity (FLI) in the nucleus accumbens,medial prefrontal cortex and lateral septal nucleus, but not in the dorsolateralstriatum..
CONCLUSION: These findings indicate that iptakalim is a drug that maypossess an atypical clozapine-like antipsychotic property with a distinct mechanismof action.
The major contributions of the present study lie in:
1. For the first time, we validated several preclinical animal models forantipsychotic activity based on repeated treatment regimen. We show that repeatedphencyclidine-induced hyperlocomotion model based on repeated antipsychotictreatment regimen is capable of capturing the progressive increase pattern ofantipsychotic treatment seen in the clinic and differentiating antipsychotics fromanxiolytics; which serve as a better model for the investigation of the neurobiologicalmechanisms of action of antipsychotic drugs and delineating the pathophysiology ofschizophrenia
2. For the first time, we explored the behavior and receptor mechanismsunderlying acute and repeated effects of antipsychotic.
3. For the first time, we determined that iptakalim is a drug that may possess anatypical clozapine-like antipsychotic property with a distinct mechanism of action,and points out that neuronal and astrocytic plasma membrane and/or mitochondrialK-ATP channels may be a target that deserves attention for antipsychotic drugdevelopment.
应用抗精神分裂症药物是目前治疗精神分裂症的主要手段。第一代抗精神分裂症药物是以氟哌啶醇为代表的经典型抗精神分裂症药物，其通过阻断多巴胺D2受体起到治疗作用。经典型抗精神分裂症药物能有效控制精神分裂症阳性症状，但对阴性症状的疗效甚差，并且长期用药会产生严重的副反应，如：锥体外系症状、性功能障碍、直立性低血压、神经内分泌紊乱及镇静，这些都限制了经典型抗精神分裂症药物的使用。第二代抗精神分裂症药物是以氯氮平、奥氮平为代表的非经典型抗精神分裂症药物。这类药物和多巴胺D2受体的结合率相对较低，但和其他受体的结合率相对较高，如：5-HT_(2A)、5-HT_(1A)、α1-肾上腺素、α2-肾上腺素受体。与经典型抗精神分裂症药物相比，非经典型抗精神分裂症药物不仅可以有效控制精神分裂症阳性症状，同时减少了发生锥体外系副反应的可能性。然而，第二代抗精神分裂症药物能产生其他的副反应，如：体重增加、二型糖尿病、高血糖症及脂质代谢障碍。另外，超过30%的精神分裂症患者对任何药物治疗均不敏感，病情持续活跃。目前抗精神分裂症药物对阴性症状疗效极其有限，同时可以产生众多副作用，因此当前精神分裂症的药物治疗现状并不乐观，迫切需要开发新的药物来缓解精神分裂症患者的阴性症状及认知障碍，以此来提高精神分裂症患者的生活质量。
动物模型在研究人类疾病及开发新药方面起着非常重要的作用，而目前有关精神分裂症的病因学及病理生理学尚未阐明。另外，这类疾病的许多症状很难在啮齿类动物上直接进行检测，如：妄想、散发性思维等，因此，建立能适当地反映精神分裂症这样具有复杂神经精神异常的动物模型非常困难。
应用动物行为学模型是研究精神分裂症及开发、筛选新型抗精神分裂症药物的最主要手段。在我们可以检测抗精神分裂症药物在患者上的作用前，我们必须首先研究药物在动物行为学上的作用。一个理想的精神分裂症动物模型的重要因素是其对于当前及未来的治疗有着较高的预测效度。然而，目前没有一种理想的动物模型能模拟所有精神分裂症患者的症状，每一种模型只能模拟精神分裂症的某个方面的特点。因此精神分裂症治疗手段的预测型模型仅仅反应抗精神分裂症药物的局限的一个方面的作用，并且在此情况下，研究者通常只是检测急性给予抗精神分裂症药物对于多巴胺或谷氨酸受体介导的行为异常的作用。还未有多次给药动物行为模型的相关报道及初步行为机制探讨。而临床上精神分裂症患者是长期服药且症状长期存在。所以迫切需要开发一些改良的精神分裂症模型来更好的反应药物对精神分裂症的治疗作用。
ATP敏感性钾通道（ATP-sensitive potassium channel，K-ATP通道）是一类耦联细胞代谢和电活动、以细胞内的ATP/ADP水平为门控因素、非电压依赖性的特殊钾离子通道。近年来，包括本实验室在内的研究表明K-ATP通道特别是线粒体K-ATP通道（mitochondrial ATP-sensitive potassium channel，mitoK-ATP通道）不仅是急性缺血缺氧、氧化应激等病理因素损伤时机体的重要内源性保护机制，而且与神经退行性疾病（neurodegenerative diseases），包括PD，阿尔茨海默病（Alzherimer’s disease, AD）相关。
新型K-ATP通道开放剂埃他卡林（Iptakalim，IPT）是我国学者自行设计、合成的脂肪仲胺类小分子化合物，最初开发用于治疗高血压，它通过开放心血管KATP通道起到抗高血压作用。后期研究表明埃他卡林可以穿透血脑屏障并作用于神经元细胞或胶质细胞膜上KATP通道及线粒体KATP通道，使得在整体动物模型上研究、评价K-ATP通道开放剂的神经系统作用成为可能。
本实验室前期研究显示盐酸埃他卡林有望用于治疗精神分裂症，有望改善精神分裂症患者的阴性症状及认知功能障碍。首先：在体或离体实验已证实盐酸埃他卡林可以抑制多巴胺的过度释放。研究表明埃他卡林可以显著抑制鱼藤酮或GBR-12909诱导PC12细胞释放多巴胺，在体微透析研究亦表明埃他卡林可以抑制MPP+或尼古丁诱导的多巴胺释放。更加让我们感兴趣的是：在单侧6-OHDA造模的PD大鼠中，埃他卡林可以显著降低健侧细胞外多巴胺水平，而显著升高损毁侧细胞外多巴胺水平，这种特征与多巴胺的部分激动剂，如：阿立哌唑，非常相似。其次，研究证实埃他卡林可以通过抗凋亡，抗坏死起到神经保护作用，这些均与埃他卡林抑制谷氨酸释放，调节谷氨酸能受体相关。另外，在动物行为学研究中发现，埃他卡林可以逆转氟哌啶醇诱导的肌僵直和低运动能力。用埃他卡林或二氮嗪（一种线粒体ATP敏感性钾通道开放剂）对动物进行预保护可以阻止鱼藤酮诱导的肌僵直，并且可以减少纹状体多巴胺含量。以上这些发现提示埃他卡林有可能可以在不同脑区对多巴胺含量进行调节，使之趋于正常水平，从而起到多巴胺稳定剂的作用。KATP通道大量存在于黑质、腹侧被盖区、前额皮质、及海马，这些区域对于神经递质如：谷氨酸，多巴胺，GABA的调节有着重要作用，并且这些区域与精神分裂症的病理生理严密相关。埃他卡林已被证实可以通过开放KATP通道而起到独特的抗高血压效果，精神分裂症患者往往伴有高血压，从而埃他卡林的这种抗高血压效果非常具有吸引力。另外，已有文献基于多巴胺受体可以调节KATP通道开放的事实作出KATP通道开放剂有望治疗精神分裂症的假设。事实上，已有研究临床研究证实，二氮嗪联合氟哌啶醇用药可以显著提高临床疗效，二氮嗪可以强化氟哌啶醇对阳性症状的控制作用，并可改善精神分裂症患者的一般精神症状。
前期研究结果提示IPT是富有前景的靶向于K-ATP通道的新型抗精神分裂症药物。然而，目前学术界尚未见K-ATP通道开放剂对精神分裂症的治疗作用的报道。
多次给药动物行为学模型是否与急性模型一致？多次给药动物模型的行为学机制是什么？K-ATP通道开放剂是否对精神分裂症动物模型有治疗作用？K-ATP通道是否是治疗精神分裂症的潜在靶点？这些科学问题的阐明，不仅开拓了神经精神的新领域，也将为发展理想的神经保护剂提供新的靶标。因此，本文工作第一部分首先应用建立多种多次给药大鼠精神分裂症行为学模型，系统研究了多次给药与急性给药模型的差异。第二部分在发现多次给药模型更优越的基础上，研究多次给药模型的相关行为学机制；第三部分研究K-ATP通道开放剂IPT在多次给药动物行为学模型中对精神分裂症的实验治疗学作用。
第一部分多次给药精神分裂症行为模型的建立及意义
目的：建立多次给药精神分裂症行为学模型，研究、阐明多次给药精神分裂症模型与急性给药模型在进行抗精神分裂症药物筛选中的差异及意义。
方法：建立多次给药快速运动大鼠模型方法：给药前两天开始适应测试环境及测试箱，自第三天起，连续5天先给予SD大鼠CLZ（5.0、10.0、20.0mg·kg~(-1)·day~(-1), s.c.）、HAL（0.01、0.05、0.10 mg·kg~(-1)·day~(-1), s.c.）、RIS（0.30、0.10mg·kg~(-1)·day~(-1), s.c.）、CDP（10.0 mg·kg~(-1)·day~(-1), i.p.）、FLU（5.0、10.0 mg·kg~(-1)·day~(-1),i.p.）或生理盐水，半小时候后给予SD大鼠AMPH（1.5 mg·kg~(-1)·day~(-1), s.c.）或PCP（3.2 mg·kg~(-1)·day~(-1), s.c.）或生理盐水。于每天第一次给药后开始记录大鼠运动情况，连续记录90分钟（含给致幻药前的30分钟及致幻药后的60分钟），连续记录5天。
建立多次给药条件躲避反射模型方法：给药前两天开始适应测试环境及测试箱，自第三天起，在连续两周时间内给予SD大鼠条件躲避反射训练十次。SD大鼠被放入一个被栅栏分隔成两部分的测试箱，大鼠可以在这两部分间自由穿过。即先给予大鼠一个信号：声音信号，然后给动物一次电击，最终使SD大鼠能把这两种刺激联系起来，从而接受到信号后可以穿越到箱子的另一边以躲避电击，形成条件躲避反射。每次训练含有二十次声音信号和电击。最后连续两天能成功躲避百分之七十以上即被认为学会了条件躲避反射，即成功躲避14次的SD大鼠进入下一阶段实验。停止训练后即连续5天给予SD大鼠CLZ（5.0、10.0、20.0 mg·kg-1·day~(-1), s.c.）或HAL（0.01、0.05、0.10 mg·kg-1·day~(-1), s.c.）或生理盐水，一小时后放入条件躲避反射测试箱测试，记录大鼠条件躲避反射次数。
结果：1）急性快速运动实验中，CLZ、HAL、OLZ均剂量依赖性地抑制AMPH或PCP诱导的运动行为增强，同时急性状态下CLZ、OLZ更倾向于抑制PCP诱导的快速运动行为，而HAL更倾向于抑制AMPH诱导的快速运动行为。2）在多次给药快速运动实验中，随着给药次数的增多，CLZ、HAL、OLZ逐渐丧失对AMPH诱导的快速运动行为的抑制能力，而在PCP诱导的快速运动行为实验中，随着给药次数的增多，CLZ、HAL、OLZ对快速运动行为的抑制能力在增强，而CDP并不能显示这种能力。3）在多次给药条件躲避反射实验中，随着给药次数的增多，HAL对SD大鼠条件躲避反射的抑制能力逐渐增强，而CLZ随着给药次数的增多，逐渐丧失对大鼠条件躲避反射的抑制能力。
结论：联合急性给药和多次给药快速运动行为学模型可以区分经典型或非经典型抗精神分裂症药物，多次给药PCP诱导的快速运动行为模型可以更好地模拟临床上的给药情况。
第二部分多次给药精神分裂症行为模型的行为机制和受体机制
目的：在建立PCP多次给药快速运动行为学模型基础上，研究、阐明多次给PCP行为学模型的行为机制。在建立HAL、CLZ多次给药条件躲避反射模型基础上，研究、阐明HAL及CLZ抑制条件躲避反射的受体学机制。
方法：在多次给予PCP动物模型上首先检测不同给药史对多次PCP诱导的快速运动行为的作用：在饲养笼内连续5天给予SD大鼠CLZ（10.0mg·kg-1·day~(-1),s.c.）或HAL（0.05mg·kg-1·day~(-1), s.c.）或OLZ（2.0 mg·kg-1·day~(-1), s.c.）或生理盐水，从第6天起连续5天先给予SD大鼠CLZ（10.0mg·kg-1·day~(-1), s.c.）或HAL（0.05mg·kg-1·day~(-1), s.c.）或OLZ（2.0 mg·kg-1·day~(-1), s.c.）或生理盐水，半小时后给予SD大鼠PCP（3.2 mg·kg-1·day~(-1), s.c.），同时于第6天起每天给药后把SD大鼠放入快速运动行为测试箱进行测试，记录大鼠运动情况，连续记录90分钟（含给PCP前的30分钟及PCP后的60分钟），连续记录5天。其次检测相同给药史前提下，不同测试环境暴露史对多次PCP诱导的快速运动行为的作用：连续7天给予SD大鼠HAL（0.03mg·kg-1·day~(-1), s.c.），半小时候给予SD大鼠PCP（1.6mg·kg-1·day~(-1), s.c.），一组于给药第一天即放入测试箱测试记录，一组在饲养笼内连续给药两天，于第三天放入测试箱测试记录，另外一组在饲养笼内连续给药四天，于第五天放入测试箱测试记录。
在多次给药条件躲避反射模型上，给药前两天开始适应测试环境及测试箱，自第三天起，在连续两周时间内给予SD大鼠条件躲避反射训练十次。训练结束后连续3天给予成功获得条件躲避反射能力的大鼠QUI（1.0mg·kg-1·day~(-1), s.c.）或DO（I 2.5mg·kg-1·day~(-1), s.c.），十分钟后分别给予SD大鼠HAL（0.05mg·kg-1·day~(-1),s.c.）或CLZ（10.0mg·kg-1·day~(-1), s.c.）或OLZ（1.0mg·kg-1·day~(-1), s.c.），抗精神分裂症药物给药半小时后放入条件躲避反射测试箱测试记录。
结果：1）有抗精神分裂症药物给药史的大鼠并不能在首次测试时达到最强抑制效果。2）在相同给药史情况下，暴露于测试环境下的次数越多，抑制快速运动行为的能力更强。3）HAL抑制条件躲避反射的能力可以被QUI所逆转，而CLZ抑制条件躲避反射的能力可以被DOI所逆转。
结论：抗精神分裂症药物对于多次PCP诱导的快速运动行为的逐渐增强效应依赖于抗精神分裂症药物与PCP的相互作用，同时亦依赖于药物与环境的相互作用。HAL通过阻断D2受体发挥抑制条件射避反射作用，而CLZ通过阻断5HT2受体发挥作用。
第三部分K-ATP通道开放剂对精神分裂症的实验治疗学作用
目的：研究、阐明K-ATP通道开放剂在多种动物行为学模型中对精神分裂症的实验治疗学作用。
方法：应用快速运动行为检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对AMPH（1.5 mg·kg-1·day~(-1)，s.c.）、PCP（3.2 mg·kg-1·day~(-1)，s.c.）诱导的快速运动行为的抑制效果，应用条件躲避反射模型检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对SD大鼠条件躲避反射的抑制效果，应用PPI模型，检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对AMPH（1.5 mg·kg-1·day~(-1)，s.c.）或PCP（3.2 mg·kg-1·day~(-1)，s.c.）诱导的PPI损害的影响。应用免疫组织化学检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）对精神分裂症相关脑区c-FOS表达的影响。应用肌僵直模型检测IPT（10、30、60mg·kg-1·day~(-1)，i.p.）本身对SD大鼠肌僵直的影响。
结果：1) IPT（60mg·kg-1·day~(-1)，i.p.）在急性状态下可以抑制AMPH、PCP诱导的快速运动行为，且更倾向于抑制PCP诱导的快速运动，与CLZ相一致，随着给药次数增多而丧失抑制能力。2) IPT（60mg·kg-1·day~(-1)，i.p.）在急性状态下可以抑制条件躲避反射，随着给药次数增多而丧失抑制能力，与CLZ相一致。3) IPT无法逆转AMPH或PCP诱导的PPI损害。4) IPT诱导的相关脑区c-FOS表达情况与CLZ相一致。5) IPT本身不影响肌僵直。
结论：K-ATP通道开放剂IPT在多种精神分裂症行为学模型中显示了一定的有效性，K-ATP通道有望成为抗精神分裂症药物开发的新靶点。
综上所述，本文工作的主要创新之处在于：
1.建立了多个多次给药动物行为学模型用于研究精神分裂症，揭示联合使用急性模型和多次给药模型或联合应用多巴胺类致幻剂和谷氨酸类致幻剂可以更好地研究、区分抗精神分裂症药物作用特点和类别。为筛选新的抗精神分裂症药物积累了必要的学术与实验基础。
2.阐明多次给药PCP快速运动模型的行为学机制，不仅依赖于药物和药物的相互作用，还依赖于药物和环境的相互作用。同时阐明HAL及CLZ在条件躲避反射中起抑制作用的受体学基础。为进一步机制研究提供了必要的学术基础。
3.发现K-ATP通道开放剂IPT对多种精神分裂症行为学模型有治疗作用，且与CLZ相似。研究结果为发展靶向于K-ATP通道的药物用于精神分裂症的临床治疗提供了理论依据。
Schizophrenia is an etiology unknown mental disorder. Onset of symptomstypically occurs in young adulthood, characterized by abnormalities in the thought,emotion and behavior. The symptoms of schizophrenia include positive and negativesymptoms, the positive symptoms most commonly manifests as hallucinations,disorganized thinking, and the negative symptoms most commonly manifests associal withdrawal and anhedonia. In addition, patients with schizophrenia also showcognitive impairment such as working memory and attention impairment.
Antipsychotic drugs (APDs) are the main medications used to treatschizophrenia. The first-generation APDs (typical APDs, e.g., haloperidol) areprimarily dopamine D2 receptor antagonists. They are most effective in the control ofpsychotic symptoms but have a high propensity for producing severe side effects,such as extrapyramidal symptoms (EPS), sexual dysfunction, orthostatic hypotension,neuroendocrine disturbances, and sedation, which limit the therapeutic usefulness ofAPDs and reduce the patient’s quality of life. The second-generation APDs (atypicalAPDs, clozapine, olanzapine) display a lower affinity for dopamine D2 receptors andhigher affinities for other receptors, such as 5-HT2A, 5-HT1A andα1- adrenergic and α2 - adrenergic receptors. In comparison to typicals, atypical APDs are equallyeffective against psychotic symptoms but have a reduced risk of EPS. However,atypicals can cause other unwanted side effects, such as weight gain, type II diabetes,hyperglycemia, and dyslipidemia. In addition, more than 30% of patients respondpoorly to any drug treatment and remain actively psychotic. Thus, it is it safe to saythat the current psychopharmacological treatments for schizophrenia areunsatisfactory because of their limited effectiveness on non-psychotic symptoms andthe disturbing side effects that they can cause. Consequently, there is a pressing needto develop better drugs that offer hope for the alleviation of negative symptoms andcognitive deficits in schizophrenia, to improve the quality of life of schizophrenicpatients.
Animal behavior models are extremely useful tools in researching pathogenesisand treatment of human disease. Creating adequate animal models of complexneuropsychiatric disorders such as schizophrenia represents a particularly difficultchallenge. In the case of schizophrenia, little is certain regarding the etiology orpathophysiology of the human disease. In addition, many symptoms of the disorderare difficult to measure directly in rodents.
Predictive validity for current and future therapies is one of the more desirablefeatures of an ideal animal model of schizophrenia. However, some current“predictive models”of schizophrenia treatment measure only a single dimension ofantipsychotic drug effects, often testing the effects of acute antipsychotic drugadministration on dopamine or glutamate receptor-mediated behaviors. Improvedmodels of schizophrenia will likely lead to unique advances in schizophreniatreatment.
ATP-sensitive potassium channel (K-ATP channel) is a special class ofpotassium channel, which links cell metabolic state to excitability. K-ATP channelsconsist of discrete pore-forming and regulatory subunits and are activated by adecrease in ATP/ADP ratio. Recently, it is demonstrated that K-ATP channelespecially mitochondrial K-ATP (mitoK-ATP) channel is the importantneuroprotective target, and may be the endogenous protective mechanism after ischemic, hypoxia or oxidative stress-induced injury. Moreover. K-ATP channelparticipates in the initiation and progress of Parkinson s disease (PD), Alzherimer'sdisease (AD')
Iptakalim was originally developed for the treatment of hypertension. It is anovel adenosine tnphosphate (ATP)-sensitive potassium channel activator that opensthe cardiovascular K-ATP channels and exerts an antihypertensive effect. Becauseiptakalim was later found to be able to easily pass through the blood-brain-barrier andto act on the neuronal plasma membrane and/or mitochondrial K-ATP channels, itspotential therapeutic effects ou neurological and neuropsychiatric disorders havegenerated much interest Current research focuses on the neuronal protective effectsof lptakalim on ischenic stroke. Parkinson s disease (PD) and its potential therapeuticeffect on nicotine addiction
Several lines of indirect evidence suggest lhat lptafcalim may be potentiallyuseful for schizophrenia and may offer needed efficacies on negative and cognitivesymptoms First, in vitro and in vivo experiments demonstrate that iptakalim has aninhibitory function on excess dopamine release. Iptakalim is found to significantlyreduce dopamine release induced by rotenone or GBR-I2909 in rat dopaminergicPC 12 cells and to attenuate dopamine release induced by1-methy1-4-phenylpyridinium ion (MPP(+)) or nicotine m freely moving ratsInterestingly, in the unilateral 6-hydroxydopamine (6-OHDA) lesioned rats (a modelof PD). iptakalim is shown to significantly decrease extracellular dopamine levels inthe intact side of the sratum. while increasing dopamine levels in the lesioned sideThis unique property in some ways resembles lhat of a dopamine partial agonist, suchas aripiprazole, and suggests that iptakalim may be capable of adjusting the level ofdopamine in different parts of the brain Second, iptakalim is demonstrated to possessan intrinsic neuroprotective effect against necrosis and apoptosis due to its ability tolimit glutamate release and receptor functions. Third, in animal behavioral studies.iptakalim is shown to reverse haloperidol-induced catalepsy and hypolocomotionPretreatment with iptakalim or diazoxide (a selective mitochondrial ATP-sensitivepotassium channel opener) can even prevent rotenone-induced catalepsy and the reduction of striatum dopamine contents. These fomdomgs, together with evidencereviewed above showing that lptakalim can inhibit excess dopamine release, stronglysuggest that iptakalim may function as a ""dopamine stabilizer to modulate theappropriate level of dopamine in different parts of the brain. It may increasedopamine release at the site where tbe dopamine level is low, while decreasingdopamine release at the site where the dopamine level is high. Fourth, iptakalim isshown to possess a unique antihypertensive effect via the opening of the K-AXPchannels in several animal models. This antihypertensive effect of iptakalim is anattractive feature because hypertension is common in patients with psychiatric illness.Interestingly, most antipsychotic drugs also have a similar hypotensive effect.although via quite different physiological mechanisms. Nevertheless, this similarityadds to the support for the proposition that iptakalim may possess an antipsychoticproperty. Fifth the target site of iptakalim -the K-ATP channel- is found in the neuralcircuits that are implicated in the pathophysiology of scluzophrenia. such as thesubstantia nigra, ventral tegmental area, the prefrontal cortex and hippocampus, andplays an important role in the regulation of release of neurotransmitters, such asglutamate. dopamine and GABA Finally, it has been hypothesized that the K-ATPchannel activators may be beneficial in schizophrenia based on the evidence thatdopamine receptors can modulate the K-ATP channel opening. Diazoxide theATP-sensitive potassium channel opener has been tried m the clinic as an adjunctivetreatment together with haloperidol. It potentiated the effects of haloperidol on thepositive and general psychopathological symptoms of schizophrenia as measured byPANSS.
In the present study, we first evaluated several rat behavioral models forantipsychotic activity. Then we used these newly developed models and exploredthe behavioral and receptor mechanisms underlying acute and repeated effects ofantipsychotic treatment Finally, we investigated the potential antipsychotic effect ofK-ATP channel opener EPT on preclinical scluzophrenia behavior model.
Part I Significance of the repeated antiphychotic treatmentschizophrenia model
AIM: To investigated whether repeated antipsychotic treatment could producean early-onset and progressively increased antagonistic effect on amphetamine orphencyclidineinduced hyperlocomotion and on conditioned avoidance response as away of assessing the validity of such models in capturing time course of antipsychoticaction.
METHODS: For the hyperlocomotion test, on each of the five consecutive testdays, different groups of rats (n=6–7/group) received an initial injection of eitherhaloperidol (0.01–0.10 mg/kg, sc), clozapine (5–20.0 mg/kg, sc), olanzapine (1.0mg/kg, sc), chlordiazepoxide (10.0 mg/kg, ip) or vehicle (sterile water, sc) 30 minprior to a second injection of either amphetamine (1.5 mg/kg, sc) or phencyclidine(3.2 mg/kg, sc). Motor activity was subsequently monitored for 60 min afteramphetamine or phencyclidine treatment. For the CAR test, on each of the fiveconsecutive test days, different groups of rats (n=6–7/group) received an injection ofeither haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or vehicle (sterilewater, sc). Conditioned avoidance response monitored 60 min after HAL、CLZ orVEH treatment.
RESULTS: 1) Repeated treatment of haloperidol, clozapine, or olanzapineprogressively potentiated inhibition on repeated phencyclidine-inducedhyperlocomotion and prolonged this action over the five consecutive days；2) Incontrast, antipsychotic inhibition on repeated amphetamine-induced hyperlocomotionwas gradually attenuated and shortened；3) Repeated treatment of chlordiazepoxide, abenzodiazepine anxiolytic, retained its inhibition on amphetamine-inducedhyperlocomotion, but had no effect on phencyclidine-induced one；4) Repeatedtreatment of haloperidol progressively potentiated inhibition on conditionedavoidance response; 5) In contrast, repeated treatment of clozapine progressivelyattenuated inhibition on conditioned avoidance response.
CONCLUSION: R e p eated phencyclidine-induced hyperlocomotion model repeated antipsychotic treatment regimen is capable of capturing theprogressive increase pattern of antipsychotic treatment seen in the clinic anddifferentiating antipsychotics from anxiolytics; thus it may serve as a better modelfor the investigation of the neurobiological mechanisms of action of antipsychoticdrugs and delineating the pathophysiology of schizophrenia.
Part II Mechanisms underlying repeated antiphychotictreatment schizophrenia model
AIM: To investigate the behavioral and receptor mechanisms underlying acuteand repeated effects of antipsychotic treatment.
METHODS: For different antipsychotic treatment history test: First, differentgroups of rats (n=6–7/group) received an injection of either haloperidol (0.05 mg/kg,sc), clozapine (5 mg/kg, sc), olanzapine (2.0 mg/kg, sc), or vehicle (sterile water, sc)in the homecages for daily for five consecutive days, then, on the next five test days,they were injected with either haloperidol (0.05 mg/kg, sc), clozapine (5 mg/kg, sc),olanzapine (2.0 mg/kg, sc), or vehicle (sterile water, sc) 30 min prior to a secondinjection of phencyclidine (3.2 mg/kg, sc) before being placed in the motor activitytesting boxes. Motor activity was monitored for 60 min after phencyclidine treatment.Some rats that received vehicle in the first five days received either haloperidol (0.05mg/kg, sc), clozapine (5 mg/kg, sc), olanzapine (2.0 mg/kg, sc) in the second test days.For different testing room exposure test: on each of 7 consecutive test days, differentgroups of rats (n=8/group) received an initial injection of either haloperidol (0.03mg/kg, sc), clozapine (5 mg/kg, sc), olanzapine (1.0 mg/kg, sc), or vehicle (sterilewater, sc) 30 min prior to a second injection of phencyclidine (1.6 mg/kg, sc) in theirhomecages or testing boxes. Motor activity was subsequently monitored for 60 minafter phencyclidine treatment.
For the CAR test: well-trained rats were administered with haloperidol (0.05 mg/kg,sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with eithersterile water, quinpirole (a selective dopamine D2/D3 agonist, 1.0 mg/kg, sc), and/or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT2A/2C agonist, 2.5 mg/kg,sc), and their avoidance behavior were tested over three consecutive days. After twodays drug-free retraining, the repeated treatment effect (i.e. drug memory) wasassessed in a challenge test.
RESULTSRESULTS: 1) Preexposure to the antipshchotic did not afftect the inhibition ofantipsychotic treatment on acute PCP-induced hyperlocomotion.; 2) Differentexposure times affect the inhibition effect of HAL, but not CLZ, OLZ, onPCP-induced hyperlocomotion；3) Pretreatment of quinpirole, but not DOI,attenuated the acute haloperidol-induced disruption of avoidance responding and to alesser extent, olanzapine-induced disruption；4) In contrast, pretreatment of DOI, butnot quinpirole, attenuated that of clozapine；5) On the repeated effect, pretreatmentof DOI attenuated the haloperidol drug memory, whereas pretreatment of quinpiroleattenuated olanzapine drug memory and potentiated that of clozapine.
CONCLUSION: The progressively potentiated inhibition of repeated treatmentof haloperidol, clozapine, or olanzapine on repeated phencyclidine inducedhyperlocomotion depends on the drug-drug interaction and drug-environmentinteraction. Acute haloperidol and olanzapine disrupt avoidance responding primarilyby immediately blocking dopamine D2 receptors, whereas acute clozapine exerts itsdisruptive effect primarily by blocking the 5-HT2A/2C receptors. The repeatedhaloperidol and clozapine effect may be mediated by brain changes initiated by5-HT2A/2C blockade, whereas the repeated olanzapine effect may be mediated by brainchanges initiated by D2 blockade.
Part III Effect of iptakalim in schizophrenia models
AIM: To examine the potential antipsychotic activity of iptakalim (IPT) inseveral schizophrenia animal behavioral models
METHODS: We used some preclinical animal behavioral model to investigatethe potential antipsychotic activity of IPT：1) amphetamine- andphencyclidine-induced hyperlocomotion；2) conditioned avoidance responding model; 3) amphetamine- and phencyclidine-induced prepulse inhibition deficit model; 4)Immunohistochemistry was taken for analyses of IPT induced C-fos expression inthe nucleus accumbens, medial prefrontal cortex, lateral septal nucleus, anddorsolateral striatum.
RESULTSRESULTS: 1) IPT is effective in reducing amphetamine- andphencyclidine-induced hyperlocomotion and shows a preferential effect in reducingthe PCP-induced hyperlocomotion over the amphetamine-induced one；2) acuteiptakalim treatment selectively and dose-dependently disrupts conditioned avoidanceresponding. Repeated iptakalim treatment gradually loses its inhibition on avoidanceresponding, an effect shared only by clozapine, but not by other antipsychotics tested,such as haloperidol, olanzapine and risperidone; 3) iptakalim itself does not disruptprepulse inhibition (PPI) of acoustic startle reflex or cause catalepsy. It potentiates theamphetamine-induced reduction of PPI but is ineffective in reversing thephencyclidine-induced disruption; 4) iptakalim and clozapine, but not haloperidol,preferentially induces Fos-like immunoreactivity (FLI) in the nucleus accumbens,medial prefrontal cortex and lateral septal nucleus, but not in the dorsolateralstriatum..
CONCLUSION: These findings indicate that iptakalim is a drug that maypossess an atypical clozapine-like antipsychotic property with a distinct mechanismof action.
The major contributions of the present study lie in:
1. For the first time, we validated several preclinical animal models forantipsychotic activity based on repeated treatment regimen. We show that repeatedphencyclidine-induced hyperlocomotion model based on repeated antipsychotictreatment regimen is capable of capturing the progressive increase pattern ofantipsychotic treatment seen in the clinic and differentiating antipsychotics fromanxiolytics; which serve as a better model for the investigation of the neurobiologicalmechanisms of action of antipsychotic drugs and delineating the pathophysiology ofschizophrenia
2. For the first time, we explored the behavior and receptor mechanismsunderlying acute and repeated effects of antipsychotic.
3. For the first time, we determined that iptakalim is a drug that may possess anatypical clozapine-like antipsychotic property with a distinct mechanism of action,and points out that neuronal and astrocytic plasma membrane and/or mitochondrialK-ATP channels may be a target that deserves attention for antipsychotic drugdevelopment.
引文
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