Translational MR Imaging in Cocaine Pharmacotherapy Development

可卡因药物疗法开发中的转化磁共振成像

基本信息

批准号：
8660674
负责人：
PONNADA A NARAYANA
金额：
$ 30.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8660674
关键词：
Abstinence Adenosine Adenosine A2A Receptor Alzheimer&apos s Disease Amides Animal Model Animals Anisotropy Astrocytes Brain Carboxylic Acids Cerebrovascular Circulation Chemicals Chronic Cocaine Cocaine Abuse Cocaine Dependence Control Animal Controlled Environment Corpus Callosum Demyelinations Development Diffusion Magnetic Resonance Imaging Dopamine Dose Glutamates Grant Histologic Histology Human Huntington Disease Image Image Analysis Immunohistochemistry Individual Institutes Ischemic Brain Injury Laboratories Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Methods Monitor Myelin Names Nerve Degeneration Neurons Parkinson Disease Pathologic Pathology Pharmaceutical Preparations Pharmacotherapy Protons Radial Rattus Relative (related person)Research Resolution Rodent Spin Labels Structure Substance abuse problem Techniques Testing Therapeutic Tissues Translational Research Treatment Efficacy age related base brain tissue brain volume cerebral atrophy cocaine use effective therapy gray matter morphometry myelination neurofilament neuronal cell body neuropathology neuroprotection neurotoxic neurotoxicity normal aging novel piperidine receptor translational study white matter white matter change

项目摘要

Recent diffusion tensor imaging (DTI) studies fnsm our laboratory and others have demonstrated significantly reduced fractional anisotropy (FA) in the corpus callosum in cocaine-dependent subjects relative to controls. The changes in FA have been interpreted as an indication of altered myelin. The specific underlying neuropathology of these white matter changes and if these pathological changes can be altered by cocaine abstinence or novel phramacotherapy, however, remain to be determined. Understanding the pathological changes between nornial, healthy individuals and cocaine-addicts is not simple because of difficulties in creating a completely controlled environment. In addition, histologic confirmation of the proposed pathologic mechanism is difficult to realize in humans. In the proposed translational studies, using multi-modal magnetic resonance imaging and end point histology in rodents treated with chronic cocaine, we will determine the effects of 1) dose of cocaine and method of administration on a) regional brain atrophy measured on high resolution structural MRI with tensor based morphometry, b) white matter pathology as measured by DTI and magnetization transfer ratio, c) regional cerebral blood flow as determined by MRI-based arterial spin labeling, and d) metabolite concentrations as determined by proton magnetic resonance spectn^scopy and 2) administration of the novel adenosine A2A receptor antagonist SYN115 on cocaine associated white matter pathology, regional brain volumes and regional cerebral blood flow. These multi-modal studies in rodents should help characterize neuropathological changes and institute rational-based treatments in human cocaine abusers.

我们实验室和其他实验室最近的扩散张量成像（DTI）研究表明，与对照组相比，可卡因依赖受试者的胼胝体分数各向异性（FA）显着降低。 FA 的变化被解释为髓磷脂改变的迹象。然而，这些白质变化的具体潜在神经病理学以及这些病理变化是否可以通过可卡因戒断或新型药物疗法来改变，仍有待确定。了解正常健康个体和可卡因成瘾者之间的病理变化并不简单，因为很难创造一个完全受控的环境。此外，所提出的病理机制的组织学证实很难在人类中实现。在拟议的转化研究中，使用多模式磁共振成像和终点组织学对慢性可卡因治疗的啮齿动物进行研究，我们将确定 1) 可卡因剂量和给药方法对 a) 高分辨率结构测量的区域脑萎缩的影响基于张量形态测量的 MRI，b) 通过 DTI 和磁化传输比测量的白质病理学，c) 通过基于 MRI 的动脉自旋标记确定的局部脑血流量，以及 d) 确定的代谢物浓度通过质子磁共振波谱检查和2)施用新型腺苷A2A受体拮抗剂SYN115对可卡因相关的白质病理学、局部脑体积和局部脑血流进行影响。这些针对啮齿类动物的多模式研究应有助于表征神经病理学变化，并为人类可卡因滥用者制定基于理性的治疗方法。