MOTOR EFFECTS OF ATYPICAL ANTIPSYCHOTICS

描述：(摘自申请人的摘要)氯氮平是一种 具有独特临床、生化和行为特征的抗精神病药物。 然而，氯氮平也会产生粒细胞缺乏症，这导致了一种强烈的 寻找其他具有类似性质的“非典型”抗精神病药物 氯氮平。先前的研究表明，对颤抖的下巴的研究 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，氯氮平通常无效 在重复的给药过程中引起下巴颤动。在……里面 此外，氯氮平的作用是抑制由 抗胆碱酯酶他克林。对他克林诱导的颌骨运动的抑制作用 氯氮平的剂量相对较低；氯氮平抑制他克林诱导的 下颌运动的ED50低于观察到的杠杆抑制 按下。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 效果不佳。在涉及重复14天注射程序的研究中， 他克林诱导颌骨抑制ED50比值的排序 动作和杠杆注入程序，按比例的顺序排列 ED50用于抑制他克林诱导的颌骨移动和杠杆按压 (从低到高)如下：氯氮平和lt；奥氮平和lt； 氟哌啶醇。这一模式与人类临床数据相一致 产生锥体外系副作用。因此，我们有理由建议 涉及颤抖下巴运动的行为研究可能对 表征作为基础的药理学特征 非典型抗精神病药物对下颌运动活动的抑制尚不确定。 尽管有相当多的证据表明抗胆碱能 氯氮平的性质可能有助于该药物的运动效应，而不是 已知5-羟色胺能拮抗剂特性的可能贡献。 鉴于研究表明5-羟色胺系统可能参与了 调节非典型抗精神病药物的一些运动效应，建议的 研究将调查5-羟色胺参与抑制的机制 下巴活动的特征。第一组研究将评估 具有5-羟色胺拮抗剂特性的其他抗精神病药物。测试将会 在急性和重复给药程序之后进行。第二组 旨在研究5-HT2a/2c的影响 拮抗他克林和氟哌啶醇所致的颌骨运动。第三组 将使用颅内药物注射来确定 5-HT2a/2c拮抗剂和非典型抗精神病药物抑制脑内基因的研究 下巴活动。总而言之，这些实验的结果将 有助于确定药理特征和大脑回路 这是氯氮平的运动效应的基础。

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.