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

• 批准号: 8004216
• 负责人: PONNADA A NARAYANA
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004216
• 关键词: Abstinence; Adenosine; Adenosine A2A Receptor; Alzheimer' 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); Resolution; Rodent; Spin Labels; Structure; 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

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弥散张量成像(DTI)研究表明，与对照组相比，可卡因依赖者胼胝体中的分数各向异性(FA)显着降低。 FA的变化被解释为髓鞘改变的迹象。然而，这些白质改变的特定潜在神经病理以及这些病理改变是否可以通过可卡因戒断或新的药物治疗而改变仍有待确定。了解正常、健康的个体和吸毒者之间的病理变化并不简单，因为在创造一个完全可控的环境方面存在困难。此外，对所提出的病理机制的组织学证实在人类中也很难实现。在拟议的翻译研究中，我们将使用多模式磁共振成像和终点组织学方法对慢性可卡因治疗的啮齿动物进行研究，以确定1)可卡因的剂量和给药方法对a)高分辨率结构磁共振用张量形态测量法测量的局部脑萎缩的影响，b)DTI和磁化转移率测量的脑白质病理，c)基于MRI的动脉自旋标记测量的局部脑血流量，d)质子磁共振波谱测定的代谢物浓度，以及2)新型腺苷A2A受体拮抗剂SYN115对可卡因相关脑白质病理、局部脑体积和局部脑血流量的影响。这些对啮齿类动物的多模式研究应该有助于确定神经病理变化的特征，并制定基于理性的人类可卡因滥用者治疗方案。