In vivo measurement of dopamine transmission in schizophrenia

精神分裂症多巴胺传递的体内测量

基本信息

批准号：
7790858
负责人：
WILLIAM G FRANKLE
金额：
$ 43.67万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-25 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7790858
关键词：
Acute Address Adolescence Advanced Development Adverse effects Affinity Agonist Amphetamines Amygdaloid structure Anterior Antipsychotic Agents Apomorphine Area Back Binding Brain region Clinical Cognition Cognitive Cognitive deficits Corpus striatum structure Data Data Set Developed Countries Disease Disinhibition Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dorsal Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Goals Hippocampus (Brain)Hour Human Hyperactive behavior Image Imaging Techniques Impaired cognition Impairment Individual Label Ligands Link Literature Measurement Measures Medial Midbrain structure N-n-propylnorapomorphine Neurobiology Neuropsychological Tests Noise Oral Administration Outcome Measure Parahippocampal Gyrus Pathway interactions Patients Performance Pharmaceutical Preparations Play Population Positron-Emission Tomography Prefrontal Cortex Publishing Raclopride Relative (related person)Resolution Role Schizophrenia Short-Term Memory Signal Transduction Structure Substantia nigra structure Symptoms Synapses Technology Temporal Lobe Testing Time Translating Ventral Striatum Ventral Tegmental Area arm burden of illness cingulate cortex cognitive function disability dopamine system effective therapy emerging adult executive function in vivo information processing mesolimbic system nerve supply nigrostriatal pathway nonhuman primate novel postsynaptic preclinical study presynaptic public health relevance putamen radioligand radiotracer receptor research study single photon emission computed tomography transmission process

项目摘要

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.

描述（由申请人提供）：多巴胺在信息处理中起着至关重要的作用，背外侧前额叶皮层（DLPFC）代表一个关键节点，其中正常多巴胺功能对于正常认知至关重要。临床前研究表明，DLPFC中最佳的多巴胺信号传导水平对于最佳认知性能是必需的。在精神分裂症中，认知中存在障碍，这些障碍与功能成像技术（例如fMRI）测量的异常DLPFC活性反复相关。尽管间接证据支持以下假设：DLPFC多巴胺传播的降低是导致精神分裂症中认知障碍和异常DLPFC活性的原因，但该假设尚未在临床人群中进行检验。此外，精神分裂症中DLPFC多巴胺功能的缺陷可能会影响皮质下多巴胺功能。大量文献表明，前额叶多巴胺活性对皮质下多巴胺活性产生抑制作用。从这些观察结果中，已经提出，在精神分裂症中，皮质多巴胺功能的缺乏可能会转化为皮质下多巴胺活性的抑制作用。同样，尚未在临床人群中检验的假设。 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皮质多巴胺功能可能转化为皮质下多巴胺活性的抑制作用。在此应用中，我们建议使用正电子发射断层扫描（PET）成像在同一受试者中研究该假设的两个臂，以测量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，本应用中概述的研究将通过评估DLPFC和纹状体子区域中的突触前多巴胺功能（苯丙胺诱导的多巴胺释放）来完整检查精神分裂症的当前多巴胺假说。在同一个体中进行这些研究将提供一个独特的数据集，在该数据集中，可以检查皮质和皮质下多巴胺之间的关系。此外，在这些受试者中进行认知测试将使我们能够探索DLPFC多巴胺传播与认知之间的关系。对这种关系的理解的改善将促进精神分裂症认知障碍的新疗法的发展。公共卫生相关性：精神分裂症是工业化国家残疾的原因，在青春期或成年初期发作，缺乏完全有效的治疗方法，这对全球疾病负担很大。认知功能的障碍代表了精神分裂症的关键临床标志，因此没有明显有效的治疗方法。在这一建议中，我们试图更好地了解精神分裂症认知异常的神经生物学；希望反过来，这将推动这些认知障碍的新型治疗方法的发展。