BIOPHYSICAL ANALYSIS OF NEUROLEPTICS' BEHAVIORAL EFFECTS

拟议的实验将使用行为学、药理学和 神经手法研究，在一个严格的量化 时尚，多巴胺阻断抗精神病药物的行为效应 毒品。使用这些药物治疗的主要限制因素 精神分裂症是一种发展中的不适和经常 在两种情况下经常出现的丧失能力的电机副作用 短期(假性帕金森症、急性肌张力障碍、静坐不能)和 长期(迟发性运动障碍)治疗。成功地消除了 这些抗精神病药物的副作用将极大地 由临床前测试程序的使用提供帮助，这些程序非常 对运动副作用敏感。这样的持续发展 以动物为基础的手术是这项提议的主要目的。 行为技术(以老鼠为对象)将包括这两种技术 允许对药物进行评估的操作性和非操作性方法 对前肢使用、舌头使用和全身姿势的影响 回应。在行为方法中，最重要的是 操作响应的力-时间波形测量。包括在内 在非手术过程中是精细马达的测量。 舔食的特点和体态的量化 梁平衡任务期间的调整。这后两个 技术使测量行为影响成为可能 通常会取消操作性反应的剂量的抗精神病药物。 药理操作将包括剂量、D1vsD2受体 阻滞剂，以及各类中枢神经系统活性药物 神经镇静剂。抗精神病药物将在慢性和慢性两种情况下接受检查 急性给药范例。在慢性给药实验中， 将进行前肢使用和舌头使用的测量 在老鼠连续生活(24小时/天)的房间里 几个月了。通过持续监控两个独立的响应 系统(前肢和舌头)从一开始给药 用氟哌啶醇癸酸酯应该可以评估这两种药物 连续给药对早发和晚发运动的影响 在一次实验中，受体在相同的受试者中被阻断。GABA 迟发性运动障碍的假说将通过分析 慢性给药大鼠黑质对GAD活性的影响 加了氟哌啶醇。神经操作的形式将是 腹外侧和背内侧纹状体的神经毒性损害。 以及这些损伤对前肢使用、舌头使用、 全身姿势调整将与 抗精神病药对这些措施的影响。

The proposed experiments will use behavioral, pharmacological, and neural manipulations to investigate, in a rigorously quantitative fashion, the behavioral effects of dopamine blocking antipsychotic drugs. The major limiting factor in using these drugs to treat schizophrenia is the development of uncomfortable and often incapacitating motor side effects that frequently arise after both short-term (pseudoparkinsonism, acute dystonia, akathisia) and long-term (tardive dyskinesia) therapy. Successful elimination of these side effects from antipsychotic drug profiles will be greatly aided by the use of preclinical test procedures that are extremely sensitive to motor side effects. Continued development of such animal-based procedures is a major aim of this proposal. Behavioral techniques (with rats as subjects) will include both operant and nonoperant methods that permit the assessment of drug effects on forelimb usage, tongue usage, and whole body postural responses. Foremost among the behavioral methods will be the measurement of force-time waveforms of operant responses. Included in the nonoperant procedures are measures of the fine motor characteristics of licking and quantification of postural adjustments during a beam balancing task. These latter two techniques make it possible to measure behavioral effects of neuroleptics at doses that usually abolish operant responding. Pharmacological manipulations will include dose, Dl vs D2 receptor blockers, and various classes of CNS-active drugs besides neuroleptics. Neuroleptics will be examined in both chronic and acute dosing paradigms. In the chronic dosing experiments, measurement of forelimb usage and of tongue usage will be conducted in chambers where the rats live continuously (24 hr/day) for several months. By continuously monitoring two separate response systems (forelimb and tongue) from the very beginning of dosing with haloperidol decanoate it should be possible to evaluate both early onset and late onset motor effects of continuous dosamine receptor blockade in the same subjects in one experiment. The GABA hypothesis of tardive dyskinesia will be addressed by assaying the substantia nigras for GAD activity in the rats treated chronically with haloperidol. Neural manipulations will be in the form of neurotoxic lesions of the ventrolateral and dorsomedial striatum. And the effects of these lesions on forelimb usage, tongue usage, and whole body postural adjustments will be compared with the effects of neuroleptics on these same measures.