Translational MR Imaging in Cocaine Pharmacotherapy Development

最近的扩散张量成像（DTI）的研究fnsm我们的实验室和其他人已经证明显着减少分数各向异性（FA）在胼胝体可卡因依赖的主题相对于对照组。 FA的变化被解释为髓鞘改变的迹象。然而，这些白色物质变化的具体潜在神经病理学以及这些病理学变化是否可以通过可卡因戒断或新型药物治疗来改变，仍有待确定。了解正常人、健康人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，在人类中难以实现对所提出的病理机制的组织学确认。在拟定的转化研究中，使用慢性可卡因治疗的啮齿动物的多模态磁共振成像和终点组织学，我们将确定1）可卡因剂量和给药方法对a）采用基于张量的形态测量法在高分辨率结构MRI上测量的局部脑萎缩，B）通过DTI和磁化传递率测量的白色物质病理学，c）通过基于MRI的动脉自旋标记测定的局部脑血流量，和d）通过质子磁共振成像测定的代谢物浓度，和2）对可卡因相关的白色病理学、局部脑体积和局部脑血流量施用新的腺苷A2 A受体拮抗剂SYN115。这些在啮齿动物中的多模式研究应该有助于描述神经病理学变化，并在人类可卡因滥用者中建立基于理性的治疗方法。

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.