The Neuroanatomy of Antipsychotic Drug Action

抗精神病药物作用的神经解剖学

• 批准号: 7093482
• 负责人: WILLIAM G FRANKLE
• 金额: $ 17.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093482
• 关键词: antipsychotic agents; chlorpromazine; clinical research; clozapine; corpus striatum; dopamine; dopamine receptor; dosage; fluorine; haloperidol; human subject; laboratory rat; neural transmission; neuroanatomy; neuropharmacology; patient oriented research; pharmacokinetics; positron emission tomography; radionuclides; receptor binding; risperidone; schizophrenia; serotonin inhibitor

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.

描述（由申请人提供）：精神分裂症的多巴胺（DA）假设提出阳性症状与DA传播的多动症有关。该假设后来通过命题来完善，该多动症的命题位于腹侧纹状体（VST）和内侧颞叶的边缘区域中。这是在临床前研究中证明的非典型抗精神病药的中溶剂选择性的支持，并且成像研究表明，与纹状体相比，这些药物在时间边缘区域中获得了更高的D2受体占用率。另一方面，脑成像研究最近表明，精神分裂症与纹状体中突触前DA活性的增加有关。此外，用高分辨率PET获得的初步数据表明，精神分裂症与联想纹状体（AST）而不是VST中的DA活性过多有关，并且AST DA多动症是可以预测对抗精神病药的快速治疗反应。这些结果表明，AST而不是在VST中的D2受体阻滞对于抗精神病药作用可能至关重要。 该职业发展计划的一般目标是通过确定典型和非典型抗精神病药的典型和非典型抗精神病药物的vST，AST和感觉运动纹状体的D2受体占用率，并将这些区域占用程度与实现棘皮动物患者的治疗性反应所需的占用程度进行比较。在特定的目标（SA）1中，将与体内结合研究结合使用MicroPET成像研究，以定义8种抗精神病药（2种典型和6种非典型）的剂量占用关系。在SA2中，具有新型示踪剂[18F] Fallypride的纹状体子区域和外生区域的成像D2受体将在人类中发展。在SA3中，将使用[18F] Fallypride测量这些区域在这些区域中通过这些区域实现的D2受体的占用率。总之，这些数据将允许测试总体假设，即对于典型和非典型药物，AST的占用率都需要实现临床反应。 该研究计划将要求候选人对PET成像和抗精神病药物药理学有复杂的了解，这对于候选人的发展至关重要，以成为使用PET的独立临床研究者。