Cortical and Striatal Dopamine Dysfunction in Addiction and Schizophrenia

描述(由申请人提供)：这是第一次重新提交K02资助金的竞争性续期提案，以支持候选人的职业发展计划。候选人的研究生涯旨在开发和使用新的脑成像方法，以更好地表征与物质滥用障碍和精神分裂症相关的神经化学变化，它们的临床相关性，以及它们与治疗策略的相关性。这个K02的第一个周期(2002到2007)集中在精神分裂症的皮质多巴胺传递成像上。这项K02应用将向一个新的方向扩展，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的多巴胺(DA)释放，这是一种与精神分裂症和成瘾有关的测量方法。很大比例的精神分裂症患者使用药物，这使他们的治疗和预后变得复杂。然而，人们对共病背后的神经基础知之甚少。申请人设计了一项计划，以评估精神分裂症患者的大麻依赖患者的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面互动。申请人选择关注大麻依赖及其与精神分裂症的共病，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。为了解决这种合并症，除了已经在进行的精神分裂症患者的研究之外，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中刺激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精确HR+，D2放射性示踪剂，[11C]拉氯普利(SA1和2)和苯丙胺范例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)和健康对照组(HC)。此外，她将继续她在精神分裂症方面的研究，通过使用安非他明范例(SA3)的[11 C]FLB457来评估皮质DA的传递。这一全面的研究计划将使候选人能够在一个新的领域发展专门知识，即药物滥用、依赖和合并症，并继续确立自己作为高级PET研究员的地位。公共卫生相关性：这项建议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)精神分裂症中皮质DA传递。所有这些都对公众健康产生了重大影响，因为共病会导致不坚持和复发，大麻的广泛使用，以及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.