Cortical and Striatal Dopamine Dysfunction in Addiction and Schizophrenia

成瘾和精神分裂症中的皮质和纹状体多巴胺功能障碍

• 批准号: 7924734
• 负责人: Anissa Abi-Dargham
• 金额: $ 12.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924734
• 关键词: Acute; Address; Adherence; Age-Years; Alcohol dependence; Alcohol or Other Drugs use; Alcoholism; Alcohols; Amphetamines; Antipsychotic Agents; Area; Binding; Brain; Brain imaging; Cannabis; Clinical; Cocaine; Cocaine Dependence; Cognitive; Comorbidity; Complex; Corpus striatum structure; Data; Data Analyses; Dependence; Development Plans; Diagnosis; Disease; Dopamine; Dopamine D2 Receptor; Dorsal; Drug usage; Equilibrium; Ethnic Origin; Functional disorder; Funding; Gender; Grant; Habits; Hand; Image; Impaired cognition; Impairment; Lead; Link; Marijuana Dependence; Marijuana Smoking; Measurement; Measures; Methodology; Methods; Modeling; National Institute of Drug Abuse; Neurobiology; Outcome; Outcome Measure; Partition Coefficient; Patients; Performance; Pharmaceutical Preparations; Phenotype; Play; Positron-Emission Tomography; Prefrontal Cortex; Psychotic Disorders; Public Health; Raclopride; Recording of previous events; Relapse; Relative (related person); Research; Research Personnel; Resistance; Resolution; Role; Schizophrenia; Smoking; Structure; Substance abuse problem; Symptoms; Synapses; TNFRSF5 gene; Testing; Ventral Striatum; Work; addiction; alpha-Methyltyrosine; career; career development; caudate nucleus; cognitive enhancement; cognitive function; craving; design; drinking; dual diagnosis; high risk; imaging modality; indexing; neurochemistry; novel; outcome forecast; problem drinker; programs; public health relevance; radiotracer; receptor; relating to nervous system; socioeconomics; transmission process; treatment strategy

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.

描述（由申请人提供）：这是针对K02赠款竞争性续签以支持候选人的职业发展计划的提案的首次重新提议。候选研究职业旨在开发和使用新颖的脑成像方法，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，其临床相关性以及它们与治疗策略的相关性。该K02（2002年至2007年）的第一个周期集中在精神分裂症中的皮质多巴胺传播上。该K02应用将朝着新的方向扩展，即精神分裂症和药物滥用之间的合并症，并将继续开发新方法的工作，以直接评估皮质中的多巴胺（DA）释放，这是与精神分裂症和成瘾有关的测量。精神分裂症患者中很大一部分会使用物质，这使他们的治疗和预后复杂化。然而，关于合并症的基础神经底物知之甚少。申请人设计了一项计划，以评估依赖大麻的精神分裂症患者的DA释放，并具有特殊的纹状体改变模型，以解释两种疾病之间的负相互作用。申请人选择专注于大麻依赖性及其与精神分裂症的合并症，因为大量数据表明该药物对精神分裂症的症状学和过程特别负面影响。为了解决合并症，除了对精神分裂症患者的持续研究外，还将进行对纹状体子结构中受刺激的DA释放的研究，在双重诊断患者，依赖大麻的患者以及匹配的健康对照组中。研究将使用高分辨率正电子发射层摄影（PET）摄像机ECAT精确HR+，D2 radiotracers，[11C] raclopride（SA1和2）和二苯丙胺范式来测量三组受试者的刺激的多巴胺释放：双重诊断患者（DD）患者（DD），CANNABIS依赖患者（CANBIS患者（CD）和健康对照（CD）和健康（HC）。此外，她将继续在精神分裂症的研究中使用[11 C] FLB457与苯丙胺范式（SA3）一起评估皮质DA传播。这项全面的研究计划将使候选人能够在滥用药物，依赖和合并症的新领域发展专业知识，并继续确立自己的高级宠物调查员。 公共卫生相关性：该提案将解决与成瘾和精神分裂症领域相关的重要领域：1）这两种疾病的合并症，2）大麻依赖性DA传播的改变，3）精神分裂症的皮质DA传播。所有这些都具有很大的公共卫生影响，因为合并症会导致不遵守和复发，大麻的使用广泛，皮质功能障碍与难以治疗症状有关。了解病理生理学将导致更好的治疗策略。