BIOPHYSICAL ANALYSIS OF NEUROLEPTIC BEHAVIORAL EFFECTS

行为和药物操作将被用来研究，在一个 严格定量的方式，多巴胺的行为效应- 受体阻断的抗精神病药物。典型抗精神病药物 产生不舒服且通常使人丧失行动能力的运动副作用 出现在短期(肌张力障碍、静坐不能、帕金森症和 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 有助于消除他们，而这项工作是这项工作的一个主要目标 求婚。将使用四种新的行为程序来 量化大鼠服用抗精神病药物的不良反应。这些是1) 具有同时测量响应力的前肢操作任务， 反应持续时间和微小目录麻痹，它们提供了对 分别为肌张力障碍、运动迟缓和静止；2)持续性 模拟运动和认知副作用的注意力任务提供了 反应时测量，并检测大鼠静坐不能；3)前肢 震颤任务，它提供了一种帕金森样效应的测量方法，并且 傅立叶方法区分典型的(氟哌啶醇)和非典型的 (氯氮平)抗精神病药；以及4)力量和节律的测量 大鼠的舌头运动，这可能提供有关两者的信息 抗精神病药引起的帕金森综合症和迟发性运动障碍。这些啮齿动物 将使用模型来探讨三个相互关联的主题：1)功能 D_1和D_2受体阻滞剂在行为学中的表达差异 在完整的大鼠中的测量；2)数量行为差异 典型的(如氟哌啶醇)和非典型的抗精神病药物(氯氮平， 利培酮、奥氮平)；以及3)评估 多巴胺受体阻滞剂和多种胆碱能、5-羟色胺能和 谷氨酸能化合物作为后者可能会减少或恶化抗神经药- 诱导大鼠的行为紊乱。

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.