BIOPHYSICAL STUDY OF ANTIPSYCHOTICS BEHAVIORAL EFFECTS

描述：（改编自研究者摘要） 抗精神病药物是一个主要的进步，较旧的药物， 诱发锥体外系副作用（EPS）。这些新药，除了 氯氮平，继续诱导EPS在更高的剂量。尽管它的上级 氯氮平治疗难治性精神分裂症的疗效 产生可测量的认知副作用以及独特的，但不是 在人类和大鼠中的类似EPS的运动效应。的过度目的 这项建议是量化大鼠和近交系小鼠的运动， 氯氮平和其他非典型抗精神病药物的认知副作用 以及继续努力定量啮齿动物中的低剂量EPS。三、 主要的行为测量程序将被使用：1） 模拟低剂量EPS的食物预期操作性微僵住症（FAOM）任务 （中断行为的不动性发作）和运动迟缓（运动减慢） 运动）; 2）持续注意任务（SAT）， 同时测量反应时间和认知表现， 类似于连续的表现任务，显示赤字特征 3）前肢震颤任务（FT），使用力传感器 技术和傅立叶分析，以量化药物引起的震颤，并检测 氯氮平的张力减退和抗震颤作用。在FAOM程序中，EPS 非典型抗精神病药物氯氮平，利培酮，舍吲哚， 将在氟哌啶醇致敏大鼠中评价奎替鲁和奥氮平。 当在FAOM任务中比较氟哌啶醇处理的近交系小鼠时， C57 b1/6小鼠表现出显着的类EP S效应，而Balb/c小鼠则表现出显着的类EP S效应 而不是遗传原因。几种近交系小鼠将被 比较，以确定菌株可能表达EPS样效应的非典型 抗精神病药物SAT程序将用于大鼠，以评估 慢性氯氮平对认知的有害影响将使用FT任务 用老鼠来探索氯氮平最近发现的戒断作用（震颤 反弹），以评估其他非典型抗精神病药对氯氮平样运动的影响 影响，并评估氯氮平的能力，抑制震颤引起的 Harcadine或毒扁豆碱。

DESCRIPTION: (Adapted from the Investigator's Abstract) The atypical antipsychotic drugs are a major advance over the older drugs that frequently induced extrapyramidal side effects (EPS). These newer drugs, except for clozapine, continue to induce EPS at higher doses. Despite its superior efficacy in the treatment of refractory schizophrenic patients, clozapine produces measurable cognitive side effects as well as distinctive, but not EPS-like, motor effects in both humans and rats. The over arching purpose of this proposal is to quantify, in rats and in inbred strains of mice, the motor and cognitive side effects of clozapine and other atypical antipsychotic drugs as well as to continue efforts to quantitate low-dose EPS in rodents. Three, primary behavioral measurement procedures will be used: 1) the food-anticipation-operant-microcatalepsy (FAOM) task that models low dose EPS (bouts of immobility that interrupt behavior) and bradykinesia (slowing of movements) in both rats and mice; 2) the sustained attention task (SAT) that concurrently measures reaction time and cognitive performance and closely resembles the continuous performance task that reveals deficits characteristic of schizophrenia; 3) the forelimb tremor task (FT) that uses force-transducer technology and Fourier analysis to quantify drug-induced tremor and detects the hypotonia and antitremor effects of clozapine. In the FAOM procedure, the EPS liability of atypical antipsychotics clozapine, risperidone, sertindole, quetiapine, and olanzapine will be evaluated in haloperidol-sensitized rats. When haloperidol-treated inbred strains of mice were compared in the FAOM task, the C57bl/6 mice showed striking EPS-like effects while the Balb/c mice did not-a result suggesting genetic causes. Several inbred strains of mice will be compared to identify strains likely to express EPS-like effects of atypical antipsychotic drugs. The SAT procedure will be used with rats to assess deleterious cognitive effects of chronic clozapine. The FT task will be used with rats to explore clozapine's recently discovered withdrawal effect (tremor rebound), to evaluate other atypical antipsychotics for clozapine-like motor effects, and to assess clozapine's ability to dampen tremor induced by harmaline or physostigmine.