MOTOR EFFECTS OF ATYPICAL ANTIPSYCHOTICS

描述：（逐字摘自申请人摘要）氯氮平是一种 抗精神病药物具有独特的临床、生化和行为特征。 然而，氯氮平也产生粒细胞缺乏症，这导致了剧烈的 寻找其他“非典型”抗精神病药物， 氯氮平先前的研究表明，对震颤性颌骨的研究 大鼠的运动可能有助于识别具有运动特性的药物 类似于氯氮平。与典型的抗精神病药物不同， 以在重复给药过程中诱导震颤性下颌运动。在 此外，氯氮平还能抑制由 抗胆碱酯酶他克林。抑制他克林诱导的下颌运动， 氯氮平发生在一个相对较低的剂量;氯氮平抑制他克林诱导 ED 50低于抑制杠杆所观察到的下颌运动 紧迫。使用急性注射程序，奥氮平和利培酮也 在抑制下颌运动方面相对有效，而氟哌啶醇 无效。在涉及重复14天注射程序的研究中， 抑制他克林诱导的颌骨的ED 50比值的等级顺序 运动和杠杆注射程序， 抑制他克林诱导的下颌运动和杠杆按压的ED 50 s为 (from最低到最高）如下：氯氮平<奥氮平<硫利达嗪< 氟哌啶醇这种模式与人类临床数据一致， 产生锥体外系副作用。因此，有理由认为， 包括颤抖的下巴运动的行为研究可能对 描述了药物的药理学特征， 非典型抗精神病药对颌运动抑制作用尚不确定。 虽然有相当多的证据表明， 氯氮平的性质可能有助于这种药物的运动效应， 已知β-肾上腺素能拮抗剂性质的可能贡献。 鉴于研究表明5-HT系统可能参与了 调解一些非典型抗精神病药的运动影响，建议 研究将调查5-HT机制在抑制 下颌运动的活动。第一组研究将评估 具有5-HT拮抗剂特性的其他抗精神病药物。测试将 在急性和重复给药程序后进行。第二组 本实验旨在研究5-HT 2a/2c对大鼠脑缺血再灌注损伤的影响 拮抗他克林和氟哌啶醇诱导的下颌运动。第三组 的拟议研究将采用颅内药物注射，以确定 5-HT 2a/2c拮抗剂和非典型抗精神病药抑制的脑部位 下颌运动活动。综合起来，这些实验的结果 有助于识别药理学特征和大脑回路， 是氯氮平运动效应的基础

DESCRIPTION: (Verbatim from the Applicant's Abstract) Clozapine is an antipsychotic drug with a unique clinical, biochemical and behavioral profile. However, clozapine also produces agranulocytosis, which has led to a vigorous search for other "atypical" antipsychotics with properties that resemble clozapine. Previous research has indicated that research on tremulous jaw movements in rats may be useful for identifying drugs with motor properties similar to clozapine. Unlike typical antipsychotics, clozapine generally fails to induce tremulous jaw movements in repeated administration procedures. In addition, clozapine acts to suppress the jaw movements induce by the anticholinesterase tacrine. The suppression of tacrine-induced jaw movements by clozapine occurs at a relatively low dose; clozapine suppressed tacrine-induced jaw movements with an ED50 lower than that observed for suppression of lever pressing. Using acute injection procedures, olanzapine and risperidone also were relatively potent at suppressing jaw movements, while haloperidol was ineffective. In studies involving repeated 14 day injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever pressing was (from lowest to highest) as follows: clozapine < olanzapine < thioridazine < haloperidol. This pattern is consistent with human clinical data on the production of extrapyramidal side effects. Thus, it is reasonable to suggest that behavioral studies involving tremulous jaw movements could be useful for characterizing the pharmacological characteristics that underlie the suppression of jaw movement activity by atypical antipsychotics are uncertain. Although there is considerable evidence indicating that the anticholinergic properties of clozapine may contribute to the motor effects of this drug, less is known about the possible contribution of serotonergic antagonist properties. In view of the studies indicating that 5-HT systems may be involved in mediating some of the motor effects of atypical antipsychotics, the proposed studies will investigate the involvement of 5-HT mechanisms in the suppression of jaw movement activity. The first group of studies will assess the effects of additional antipsychotic drugs that have 5-HT antagonist properties. Tests will be conducted after both acute and repeated dosing procedures. The second group of proposed experiments is designed to investigate the effects of 5-HT2a/2c antagonism on tacrine- and haloperidol-induced jaw movements. The third group of proposed studies will employ intracranial drug injections to determine that brain loci at which 5-HT2a/2c antagonists and atypical antipsychotics suppress jaw movements activity. Taken together, the results of these experiments will help to identify the pharmacological characteristics and brain circuits that underlie the motor effects of clozapine.