Biophysical Study of Antipsychotics Behavioral Effects

精神分裂症是一种慢性精神障碍，具有遗传和环境根源，是一个主要的世界健康问题，影响到1%的人口，无论文化或地理位置如何。大脑多巴胺系统的功能障碍与这些症状有关，安非他明，一种刺激大脑多巴胺活性的药物，可以在人类中产生类似精神分裂症的精神病。抗精神病药物可以改善自发性精神分裂症和安非他明诱导的精神分裂症的症状，但会引起令人烦恼的副作用，疗效有限。因此，寻找无副作用的抗精神病药物仍在继续。提出的工作的目的是通过引入一种新的方法和一个新发现的现象，这一研究竞技场加速药物研究。新的方法是力板动作计，一种具有高时间和空间分辨率的量化行为的仪器。这项新发现涉及安非他明诱导的大鼠集中刻板行为的节律模式，这是一种长期使用但迄今为止量化不佳的实验室模型，用于评估抗精神病药物的潜力。我们现在知道，集中的刻板印象的特点是持续的，精确调节的，10赫兹有节奏的头部运动，而大鼠保持不动。我们的数据表明，非典型抗精神病药物氯氮平减缓苯丙胺诱导的节律，而不恢复运动，而其他药物有明显不同的配置文件。四个具体目标是：1）确定其他非典型抗精神病药物在安非他明处理的大鼠中是否具有氯氮平样节律减慢特性; 2）使用选择性药理学工具来减少哪些神经递质受体系统参与节律控制; 3）在遗传上不同的大鼠品系中建立10-Hz节律的普遍性及其由氯氮平的调节;和4）使用操作-测力-平板混合仪器来测量抗精神病药物恢复被安非他明破坏的习得的适应性行为的能力，并同时量化由抗精神病药物产生的运动副作用。这些结果将提高我们对多巴胺相关行为药理学基础的了解，并有助于发现改进的抗精神病药物。

DESCRIPTION (provided by applicant): Schizophrenia, a chronic mental disorder with both genetic and environmental origins, is a major world health problem affecting up to 1% of the population regardless of culture or geographic location. Dysfunctions in brain dopamine systems are implicated in the symptoms, and amphetamine, a drug that stimulates brain dopamine activity, can produce a schizophrenia-like psychosis in humans. Antipsychotic drugs ameliorate the symptoms of spontaneously occurring and amphetamine-induced schizophrenia, but cause bothersome side effects and have limited efficacy. Hence, the search for side-effect-free antipsychotics continues. The purpose of the proposed work is to accelerate drug research by introducing a new method and a newly discovered phenomenon to this research arena. The new method is the force-plate actometer, an instrument that quantifies behavior with high temporal and spatial resolution. The new discovery involves the rhythmic pattern of amphetamine-induced focused stereotypies in rats, a long used, but heretofore poorly quantified, laboratory model for evaluating antipsychotic drug potential. We now know that the focused stereotypies are characterized by sustained, precisely regulated, 10-Hz rhythmic head movements while the rat remains immobile. Our data indicates that the atypical antipsychotic drug clozapine slows the amphetamine-induced rhythm without restoring locomotion, while other drugs have distinctly different profiles. The 4 specific aims are: 1) to determine if other atypical antipsychotic drugs have the clozapine-like rhythm-slowing property in the amphetamine-treated rat; 2) to use selective pharmacological tools to reduce which neurotransmitter receptor systems participate in the rhythm control; 3) to establish the generality of the 10-Hz rhythm and its modulation by clozapine in genetically distinct rats strains; and 4) to use an operant-force-plate hybrid instrument to measure the ability of the antipsychotic drugs to restore learned, adaptive behavior disrupted by amphetamine and to quantify concurrently motor side effects produced by the antipsychotic drugs. The results will improve our understanding of the pharmacological basis of dopamine related behaviors and assist in the discovery of improved antipsychotic medications.