In vivo measurement of dopamine transmission in schizophrenia

描述(申请人提供)：多巴胺在信息处理中起关键作用，背外侧前额叶皮质(DLPFC)是一个关键节点，正常的多巴胺功能对正常认知至关重要。临床前研究表明，DLPFC中最佳水平的多巴胺信号对于最佳认知能力是必要的。在精神分裂症患者中，认知存在障碍，这些障碍与用功能成像技术(如功能磁共振)测量的异常DLPFC活动反复相关。虽然间接证据支持这一假说，即DLPFC多巴胺传递减少是精神分裂症患者认知障碍和DLPFC活动异常的原因，但这一假说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会影响皮质下多巴胺功能。大量文献表明，前额叶的多巴胺活动对皮质下的多巴胺活动有抑制作用。从这些观察中，有人提出，在精神分裂症中，皮质多巴胺功能的缺陷可能会转化为皮质下多巴胺活动的解除抑制；同样，这一假设尚未在临床人群中得到验证。因此，目前对精神分裂症多巴胺功能的看法认为：从中脑到皮质下结构的中脑边缘多巴胺投射可能过度活跃，并导致疾病的积极症状，而中皮质多巴胺投射不足导致精神分裂症患者观察到的认知障碍，这种多巴胺失衡可能与此有关，因为皮质多巴胺功能不足可能转化为皮质下多巴胺活动的去抑制。在这一应用中，我们建议在同一受试者中研究这一假说的两个方面，使用正电子发射断层扫描(PET)成像来测量DLPFC和纹状体中的多巴胺传递。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和纹状体亚区的突触前多巴胺功能(苯丙胺诱导的多巴胺释放)，对目前精神分裂症的多巴胺假说提供完整的检验。在相同的个体中进行这些研究将提供一个独特的数据集，在其中可以检查皮质和皮质下多巴胺传递之间的关系。此外，在这些相同的受试者中进行认知测试将使我们能够探索DLPFC多巴胺传递和认知之间的关系。对这一关系认识的提高将推动治疗精神分裂症认知障碍的新疗法的发展。 与公共卫生相关：在工业化国家，精神分裂症是导致残疾的最主要疾病之一，它在青春期或成年早期发病，缺乏完全有效的治疗方法，极大地加重了全球疾病负担。认知功能障碍是精神分裂症的一个关键临床标志，目前还没有明显有效的治疗方法。在这项建议中，我们试图更好地了解精神分裂症认知异常背后的神经生物学；希望反过来，这将推动这些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.