Neuroanatomy of Antipsychotic Drug Action

描述（由申请人提供）：精神分裂症的多巴胺（DA）假说提出阳性症状与DA传递过度活跃相关。这一假设后来被一个命题所完善，这个DA过度活跃位于腹侧纹状体（VST）和内侧颞叶的边缘区。这一点得到了非典型抗精神病药物的中脑边缘选择性的支持，在临床前研究中得到了证实，并且成像研究表明，与纹状体相比，这些药物在颞叶边缘区实现了更高的D2受体占有率。另一方面，最近的脑成像研究表明，精神分裂症与纹状体突触前DA活性增加有关。此外，高分辨率PET获得的初步数据表明，精神分裂症与关联纹状体（AST）而不是VST中的DA活性过度相关，并且AST DA活性过度可预测抗精神病药物的快速治疗反应。这些结果表明，D2受体阻滞剂在AST，而不是在VST，可能是关键的抗精神病药物的作用。 本职业发展计划的总体目标是进一步评估这一命题，通过确定D2受体占用的VST，AST和感觉运动纹状体的大鼠典型和非典型抗精神病药物给药后，并比较这些区域占用的程度所需的占用精神分裂症患者的治疗反应。在特定目标（SA）1中，microPET成像研究将与离体结合研究相结合，以定义8种抗精神病药物（2种典型和6种非典型）的剂量占用关系。在SA2中，将在人类中开发具有新型示踪剂[18F]fallypride的纹状体亚区和纹状体外区中的D2受体成像。在SA3中，将使用[18 F]fallypride测量精神分裂症治疗期间这些药物在这些区域中实现的D2受体占用。总之，这些数据将允许检验总体假设，即对于典型和非典型药物，AST中的占用率是实现临床应答所必需的。 研究计划将要求候选人发展PET成像和抗精神病药物药理学的复杂理解，这些技能对于候选人成为使用PET的独立临床研究者至关重要。

DESCRIPTION (provided by applicant): The dopamine (DA) hypothesis of schizophrenia proposed that positive symptoms are associated with hyperactivity of DA transmission. This hypothesis was later refined by the proposition this DA hyperactivity was localized in the ventral striatum (VST) and the limbic regions of the medial temporal lobe. This was supported by the mesolimbic selectivity of atypical antipsychotic drugs, demonstrated in preclinical studies, and by imaging studies suggested that these drugs achieve higher D2 receptor occupancy in temporal limbic regions compared to striatum. On the other hand, brain imaging studies have recently demonstrated that schizophrenia is associated with increased presynaptic DA activity in the striatum. Furthermore, preliminary data obtained with high resolution PET suggest that schizophrenia is associated with excessive DA activity in the associative striatum (AST) rather than in the VST, and that AST DA hyperactivity is predictive of fast treatment response to antipsychotic drugs. These results suggest that D2 receptor blockade in the AST, rather than in the VST, might be critical for antipsychotic action. The general goal of this career development plan is to further evaluate this proposition, by determining D2 receptor occupancy in the VST, AST and sensorimotor striatum of the rat following administration of typical and atypical antipsychotic drugs, and to compare these regional occupancies to the degree of occupancy required to achieve a therapeutic response in patients with schizophrenia. In specific aim (SA) 1, microPET imaging studies will be combined with ex vivo binding studies to define the dose-occupancy relationship of 8 antipsychotic drugs (2 typical and 6 atypical). In SA2, imaging D2 receptors in striatal subregions and extrastriatal regions with the novel tracer [18F]fallypride will be developed in humans. In SA3, occupancy of D2 receptors achieved in these regions by theses drugs during treatment of schizophrenia will be measured with [18F]fallypride. Together, these data will permit testing the overarching hypothesis that, for both typical and atypical drugs, occupancy in the AST is required to achieve clinical response. The research plan will require the candidate to develop a sophisticated understanding of PET imaging and antipsychotic medication pharmacology, skills that will be essential in the candidate's development toward becoming an independent clinical investigator using PET.