Biophysical Study of Antipsychotics Behavioral Effects

描述(申请人提供)：精神分裂症是一种慢性精神疾病，有遗传和环境两方面的原因，是一个主要的世界健康问题，影响多达1%的人口，无论文化或地理位置。这些症状与大脑多巴胺系统功能障碍有关，而苯丙胺，一种刺激大脑多巴胺活动的药物，可能会在人类中产生精神分裂样精神病。抗精神病药物可以改善自发性精神分裂症和苯丙胺性精神分裂症的症状，但会产生令人不安的副作用，疗效有限。因此，寻找无副作用的抗精神病药物的工作仍在继续。这项拟议工作的目的是通过将一种新的方法和新发现的现象引入这一研究领域，以加速药物研究。新的方法是力板活力计，这是一种以高时间和空间分辨率量化行为的工具。这项新发现涉及安非他明诱导的大鼠集中刻板印象的节律模式，这是一种长期使用但迄今量化较差的实验室模型，用于评估抗精神病药物的潜力。我们现在知道，聚焦的刻板印象的特征是持续的、精确调节的、10赫兹的有节奏的头部运动，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了苯丙胺诱导的节律，但不能恢复运动，而其他药物的曲线明显不同。这4个具体目标是：1)确定其他非典型抗精神病药物在苯丙胺治疗的大鼠中是否具有氯氮平样的节律减慢特性；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)在遗传不同的大鼠品系中建立10-HZ节律的普遍性以及氯氮平对其调制；以及4)使用操作力-平板混合仪器来测量抗精神病药物恢复被苯丙胺破坏的学习、适应行为的能力，并对抗精神病药物同时产生的运动副作用进行量化。这一结果将提高我们对多巴胺相关行为的药理学基础的理解，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.