The Neuroanatomy of Antipsychotic Drug Action

描述(申请人提供)：精神分裂症的多巴胺(DA)假说认为阳性症状与DA传递的过度活跃有关。这一假说后来被这一命题进一步完善，即这种DA过度活动定位于内侧颞叶的腹侧纹状体(VST)和边缘区域。这得到了非典型抗精神病药物的中脑边缘选择性的支持，这在临床前研究中得到了证实，而且成像研究表明，与纹状体相比，这些药物在颞叶边缘区域获得了更高的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中突触前DA活性的增加有关。此外，高分辨率正电子发射计算机断层扫描获得的初步数据表明，精神分裂症与联合纹状体(AST)而不是VST中DA活性过高有关，并且AST DA活性过高预示着抗精神病药物的快速治疗反应。这些结果表明，D2受体在AST而不是VST中的阻断可能是抗精神病作用的关键。 这一职业发展计划的总体目标是进一步评估这一命题，通过测定在给予典型和非典型抗精神病药物后大鼠的VST、AST和感觉运动纹状体中D2受体的占有率，并将这些区域占有率与精神分裂症患者达到治疗反应所需的占有率进行比较。在特定目标(SA)1中，将结合体外结合研究来确定8种抗精神病药物(2种典型药物和6种非典型药物)的剂量-占用关系。在SA2中，将在人类中开发使用新型示踪剂[18F]FolyPride对纹状体亚区和纹状体外区域的D2受体进行成像。在SA3中，这些药物在精神分裂症治疗期间在这些区域获得的D2受体的占有率将用[18F]FolyPride进行测量。总而言之，这些数据将允许检验压倒一切的假设，即对于典型和非典型药物，需要占用AST才能达到临床疗效。 研究计划将要求应聘者对PET成像和抗精神病药物药理学有深入的了解，这些技能对于应聘者成为一名使用PET的独立临床研究员至关重要。

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.