Cortical and Striatal Dopamine Dysfunction in Addiction and Schizophrenia

描述（由申请人提供）：这是为支持候选人职业发展计划的K02补助金竞争性续期的第一次重新提交提案。候选人的研究方向是开发和使用新的脑成像方法，以更好地表征与药物滥用障碍和精神分裂症相关的神经化学改变，它们的临床相关性以及它们与治疗策略的相关性。该K02的第一个周期（2002年至2007年）集中在精神分裂症皮质多巴胺传递的成像上。这种K02的应用将扩展到一个新的方向，即精神分裂症和药物滥用之间的共病，并将继续开发新的方法来直接评估皮层中多巴胺（DA）的释放，这是一种与精神分裂症和成瘾相关的测量方法。很大一部分精神分裂症患者使用药物，这使他们的治疗和预后复杂化。然而，人们对合并症背后的神经基质知之甚少。申请人设计了一个程序来评估大麻依赖精神分裂症患者的DA释放，并使用特定的纹状体改变模型来解释两种情况之间的负相互作用。申请人选择关注大麻依赖及其与精神分裂症的合并症，因为大量数据表明这种药物对精神分裂症的症状和病程有特别负面的影响。为了解决合并症，除了已经在精神分裂症患者中进行的研究外，还将在双重诊断患者、大麻依赖患者和匹配的健康对照中进行纹状体亚结构内刺激DA释放的研究。研究将使用高分辨率正电子发射断层扫描（PET）相机ECAT EXACT HR+， D2放射性示踪剂，[11C]raclopride （SA1和2）和安非他明模式来测量三组受试者的刺激多巴胺释放：双重诊断患者（DD），大麻依赖患者（CD）和健康对照（HC）。此外，她将继续她在精神分裂症中的研究，通过使用[11 C]FLB457和安非他明范式（SA3）来评估皮质DA传递。这项全面的研究计划将使候选人能够在药物滥用，依赖和共病的新领域发展专业知识，并继续建立自己作为高级PET调查员的地位。公共卫生相关性：本提案将涉及与成瘾和精神分裂症领域相关的重要领域：1)这两种疾病的共病，2)大麻依赖中DA传递的改变，3)精神分裂症中的皮质DA传递。所有这些都对公众健康产生了巨大的影响，因为合并症会导致不坚持和复发，大麻的使用很普遍，皮质功能障碍与难以治疗的症状有关。了解病理生理学将导致更好的治疗策略。

DESCRIPTION (provided by applicant): This is the first resubmission of a proposal for the competitive renewal of a K02 grant to support the career development plan of the candidate. The candidate research career is directed toward developing and using novel brain imaging methods to better characterize neurochemical alterations associated with substance abuse disorders and schizophrenia, their clinical correlates, and their relevance to treatment strategies. The first cycle of this K02 (2002 to 2007) was focused on imaging cortical dopamine transmission in schizophrenia. This K02 application will expand in a new direction, which is that of comorbidity between schizophrenia and substance abuse, and will continue the work of developing new methodology to directly assess dopamine (DA) release in the cortex, a measurement relevant to both schizophrenia and addiction. A great proportion of patients with schizophrenia use substances, which complicates their treatment and prognosis. Yet, little is known about the neural substrates underlying comorbidity. The applicant has designed a program to assess DA release in cannabis dependent patients with schizophrenia, with a particular model of striatal alterations to explain a negative interactivity between the two conditions. The applicant chose to focus on cannabis dependence and its comorbidity with schizophrenia because of the wealth of data suggesting a particularly negative effect of this drug on schizophrenia's symptomatology and course. In order to address the comorbidity, studies of stimulated DA release within the striatal substructures, in dual diagnosis patients, cannabis dependent patients, and matched healthy controls will be undertaken, in addition to the already ongoing studies in patients with schizophrenia. Studies will use the high-resolution Positron Emission Tomography (PET) camera ECAT EXACT HR+, D2 radiotracers, [11C]raclopride (SA1 and 2) and the amphetamine paradigm to measure stimulated dopamine release in three groups of subjects: Dual Diagnosis patients (DD), Cannabis Dependent patients (CD), and Healthy Controls (HC). In addition she will continue her studies in schizophrenia to assess cortical DA transmission by using [11 C]FLB457 with the amphetamine paradigm (SA3). This comprehensive research plan will allow the candidate to develop expertise in a new area that of substance abuse, dependence and comorbidity, as well as continue to establish herself as a senior PET investigator. PUBLIC HEALTH RELEVANCE: This proposal will address important areas relevant to the fields of addiction and schizophrenia: 1) the comorbidity of these two disorders, 2) the alterations of DA transmission in cannabis dependence, 3) cortical DA transmission in schizophrenia. All these have great public health impact because comorbidity leads to non adherence and relapse, marijuana's use is widespread, and cortical dysfunction is associated with difficult to treat symptoms. Understanding the pathophysiology will lead to better treatment strategies.