BIOPHYSICAL ANALYSIS OF NEUROLEPTIC BEHAVIORAL EFFECTS

神经抑制行为效应的生物物理学分析

• 批准号: 2430927
• 负责人: STEPHEN Cletius FOWLER
• 金额: $ 12.45万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2430927
• 关键词: anticholinergic agent; antipsychotic agents; attention; behavior test; biophysics; catalepsy; clozapine; dopamine antagonists; dopamine receptor; dosage; drug administration rate /duration; drug adverse effect; drug interactions; extrapyramidal disorder; haloperidol; laboratory rat; limb movement; neuropharmacology; operant conditionings; psychomotor function; psychomotor reaction time; psychopharmacology; risperidone; tardive dyskinesia; tongue; tremor

Behavioral and pharmacological manipulations will be used to study, in a rigorously quantitative fashion, the behavioral effects of dopamine- receptor-blocking antipsychotic drugs. Typical antipsychotic drugs produce uncomfortable and often incapacitating motor side effects that arise after both short-term (dystonia, akathisia, Parkinsonism, and cognitive impairments) and long-term (tardive dyskinesia and other tardive symptoms) therapy. Preclinical research into these side effects will contribute to their elimination, and such work is a major aim of this proposal. Four kinds of novel behavioral procedures will be used to quantify the adverse effects of neuroleptics in rats. These are 1) forelimb operant task with concurrent measurement of response force, response duration, and microcatalepsy, which provide descriptions of dystonia, bradykinesia, and immobility, respectively; 2) the sustained attention task, which models motor and cognitive side effects, provides reaction time measures, and detects akathisia in rats; 3) the forelimb tremor task, which affords a measure of Parkinson-like effects and with Fourier methods distinguishes between typical (haloperidol) and atypical (clozapine) neuroleptics; and 4) the measurement of force and rhythm of rats' tongue movements, which may provide information relevant to both neuroleptic-induced Parkinsonism and tardive dyskinesia. These rodent models will be used to pursue three interrelated themes: 1) functional differences between D1 and D2 receptor blockers as expressed in behavioral measures in intact rats; 2) quantitative behavioral differences between typical (e.g., haloperidol) and atypical neuroleptics (clozapine, risperidone, olanzapine); and 3) assessment of the interaction between dopamine receptor blockers and a variety of cholinergic, serotonergic, and glutamatergic compounds as the latter may lessen or worsen neuroleptic- induced behavioral disruptions in rats.

行为和药理学操作将用于研究，在一个 严格的定量方式，多巴胺的行为效应， 受体阻断抗精神病药物 典型抗精神病药物 产生不舒服和经常使人丧失能力的运动副作用， 在短期（肌张力障碍、静坐不能、帕金森综合征和 认知障碍）和长期（迟发性运动障碍和其他迟发性 症状）治疗。 对这些副作用的临床前研究将 有助于消除它们，这项工作是本组织的一个主要目标。 提议 四种新颖的行为程序将被用来 量化神经抑制剂对大鼠的不良影响。 这是1） 前肢操作任务与反应力的同时测量， 反应持续时间，和微僵住症，这提供了描述 分别为肌张力障碍、运动迟缓和不动; 2）持续的 注意力任务，模型运动和认知副作用，提供 反应时间测量，并检测大鼠静坐不能; 3）前肢 震颤任务，它提供了帕金森样效应的测量， 傅立叶方法区分典型（氟哌啶醇）和非典型 （氯氮平）精神抑制剂;和4）测量的力量和节奏， 大鼠的舌头运动，这可能提供相关的信息， 抗精神病药诱发的帕金森症和迟发性运动障碍。 这些啮齿动物 模型将用于追求三个相互关联的主题：1）功能 D1和D2受体阻滞剂之间的差异，表现为行为 完整大鼠的测量; 2） 典型的（例如，氟哌啶醇）和非典型精神抑制剂（氯氮平， 利培酮、奥氮平）;以及3）评估 多巴胺受体阻滞剂和各种胆碱能、多巴胺能和 因为后者可能会减轻或加重神经抑制剂- 导致大鼠行为紊乱。