In vivo measurement of dopamine transmission in schizophrenia

描述（由申请人提供）：多巴胺在信息加工中起着关键作用，其中背外侧前额叶皮层（DLPFC）是一个关键节点，正常的多巴胺功能对正常的认知至关重要。临床前研究表明，DLPFC中多巴胺信号的最佳水平是最佳认知表现所必需的。精神分裂症患者存在认知障碍，这些障碍与功能成像技术（如fMRI）测量的DLPFC异常活动反复相关。虽然间接证据支持DLPFC多巴胺传递减少是精神分裂症患者认知障碍和DLPFC异常活动的原因，但这一假设尚未在临床人群中得到验证。此外，精神分裂症患者DLPFC多巴胺功能缺陷可能影响皮质下多巴胺功能。大量文献表明，前额叶多巴胺活动对皮层下多巴胺活动具有抑制作用。根据这些观察，有人提出，在精神分裂症中，皮质多巴胺功能的缺乏可能转化为皮质下多巴胺活性的去抑制；这一假设还没有在临床人群中得到验证。因此，目前关于多巴胺在精神分裂症中的作用的观点提出：从中脑到皮层下结构的中脑边缘多巴胺投射可能过度活跃并导致疾病的阳性症状，而中脑皮层多巴胺投射低活性导致精神分裂症中观察到的认知障碍，这种多巴胺失衡可能相关，因为皮层多巴胺功能的缺乏可能转化为皮层下多巴胺活动的去抑制。在这项应用中，我们建议在同一受试者中研究这一假设的两个方面，使用正电子发射断层扫描（PET）成像来测量多巴胺在DLPFC和纹状体中的传递。受试者还将参加认知测试。如果成功，本申请中概述的研究将通过评估DLPFC和纹状体亚区突触前多巴胺功能（安非他明诱导的多巴胺释放），为目前的精神分裂症多巴胺假说提供一个完整的检验。在同一个体中进行这些研究将提供一个独特的数据集，其中可以检查皮层和皮层下多巴胺传递之间的关系。此外，对这些受试者进行认知测试将使我们能够探索DLPFC多巴胺传递与认知之间的关系。对这种关系的理解的改进将促进精神分裂症认知障碍的新治疗方法的发展。

DESCRIPTION (provided by applicant): Dopamine plays a critical role in information processing, with the dorsolateral prefrontal cortex (DLPFC) representing a key node in which normal dopamine function is crucial for normal cognition. Preclinical studies have shown that optimum levels of dopamine signaling in the DLPFC are necessary for optimum cognitive performance. In schizophrenia, impairments exist in cognition and these impairments repeatedly correlate with abnormal DLPFC activity measured with functional imaging techniques such as fMRI. Although indirect evidence supports the hypothesis that decreased DLPFC dopamine transmission is responsible for both the cognitive impairments and the abnormal DLPFC activity in schizophrenia, this hypothesis has yet to be tested in a clinical population. Moreover, a deficit in DLPFC dopamine function in schizophrenia may impact subcortical dopamine function. An abundant literature suggests that prefrontal dopamine activity exerts an inhibitory influence on subcortical dopamine activity. From these observations, it has been proposed that, in schizophrenia a deficiency in cortical dopamine function might translate into disinhibition of subcortical dopamine activity; again, a hypothesis not yet tested in a clinical population. Thus, the current view of dopamine function in schizophrenia proposes that: mesolimbic dopamine projections from the midbrain to subcortical structures might be hyperactive and contribute to the positive symptoms of the illness while hypoactive mesocortical dopamine projections contribute to the cognitive impairments observed in schizophrenia and that this dopamine imbalance might be related, inasmuch as a deficiency in cortical dopamine function might translate into disinhibition of subcortical dopamine activity. In this application we propose to investigate both arms of this hypothesis, in the same subjects, using positron emission tomography (PET) imaging to measure dopamine transmission in the DLPFC as well as the striatum. Subjects will also participate in cognitive testing. If successful, the studies outlined in this application will provide a complete examination of the current dopamine hypothesis of schizophrenia by assessing presynaptic dopamine function (amphetamine-induced dopamine release) in both the DLPFC and striatal subregions. Performing these studies in the same individuals will provide a unique dataset in which the relationship between cortical and subcortical dopamine transmission can be examined. Furthermore, performing cognitive testing in these same subjects will allow us to explore the relationship between DLPFC dopamine transmission and cognition. Improvements in the understanding of this relationship will advance the development of novel treatments for the cognitive impairments in schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia ranks among the top diseases as a cause of disability in industrialized nations and, with onset in adolescence or early adulthood and the lack of fully effective treatments, contributes greatly to the global burden of disease. Impairment in cognitive function represents a key clinical hallmark of schizophrenia, for which there is no clearly effective treatment. In this proposal we seek to better understand the neurobiology underlying the cognitive abnormalities in schizophrenia; with the hope that, in turn, this will advance the development of novel treatments for these cognitive impairments.