BIOPHYSICAL ANALYSIS OF NEUROLEPTICS' BEHAVIORAL EFFECTS

拟议的实验将使用行为，药理学， 神经操作进行调查，在一个严格的定量 时尚，多巴胺阻断抗精神病药的行为效应 毒品 使用这些药物治疗的主要限制因素是 精神分裂症是不舒服的发展， 使运动功能丧失的副作用， 短期（假性帕金森综合征、急性肌张力障碍、静坐不能）和 长期（迟发性运动障碍）治疗。 成功消除 这些抗精神病药物的副作用将大大 通过使用临床前测试程序， 对运动副作用敏感 继续发展这种 基于动物的程序是该提案的一个主要目标。 行为技术（以大鼠为受试者）将包括 允许评估药物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 应答 在行为方法中，最重要的是 测量操作性反应的力-时间波形。 包括 在非手术过程中， 舔的特征和姿势的量化 在梁平衡任务期间进行调整。 这后两 技术使测量行为影响成为可能， 剂量足以消除操作性反应的精神抑制剂 药理学操作将包括剂量、Dl相对于D2受体 阻滞剂，以及除此之外的各种CNS活性药物 神经抑制剂 精神抑制剂将在慢性和 急性给药模式。 在慢性给药实验中， 测量前肢使用和舌头使用 在大鼠连续生活（24小时/天）的室中， 几个月 通过连续监测两种不同的反应， 系统（前肢和舌头）从给药开始 对于氟哌啶醇癸酸酯， 持续剂量胺的早发性和迟发性运动效应 受体阻滞剂的实验中。的GABA 迟发性运动障碍的假设将通过测定 长期给药大鼠黑质GAD活性 氟哌啶醇 神经操纵将以 腹外侧和背内侧纹状体的神经毒性病变。 以及这些损伤对前肢使用，舌头使用， 全身姿势调整将与 神经抑制剂对这些指标的影响。

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.