Assessing Glutamate Homeostasis in Cocaine Addiction Using 7T 1H-MRS

项目摘要 在治疗可卡因成瘾方面，复发仍然是一个严重的未得到满足的挑战。虽然许多人将在 开始戒毒，绝大多数可卡因滥用者将在 他们的疾病，许多人将无法实现持久的无毒生存。因此，目前缺乏药物 减少复发风险仍然是可卡因依赖临床管理中的一大差距。 大量基础研究指出，谷氨酸(GLU)在神经适应中起着核心作用 以及恢复多次吸食可卡因。特别是，卡利瓦斯及其同事的临床前工作 提出了一个引人注目的模型，通过这个模型，大脑皮质下(即伏隔核或NAcc)下的GLU 传播是动物对恢复药物寻求的脆弱性的原因。此GLU的相关性 然而，CD患者的动态平衡假说[14]仍在很大程度上未经检验，这是因为缺乏临床-- 能够测量人类腹侧纹状体(VS)中GLU水平的翻译工具。 我们的成员在高场(7特斯拉)、质子磁共振波谱(1H-MRS)方面的创新 研究小组现在建议直接测量人类VS的大脑GLU的可行性。因此， 当前的探索性/开发性R21应用程序寻求将这些进展适应和应用于 一种可靠、实用、经济、客观的血糖稳态失调生物标志物的开发 人类，一个可以直接和有效地为CD患者评估候选药物的人。 如果实现，目前的研究将为未来前瞻性的、受控的、生物标志物引导的研究奠定基础 旨在恢复人群中GLU稳态的候选药物疗法的评估，以及 甚至是个性化的医疗基础。

Project Summary Relapse remains a critical unmet challenge in the treatment of cocaine addiction. While many will succeed in initiating abstinence, the vast majority of cocaine abusers will experience multiple relapses over the course of their illness, and many will fail to achieve an enduring drug-free existence. Thus, the current lack of medications for reducing relapse risk remains a major gap in the clinical management of cocaine dependence. A large body of basic research points to glutamate (GLU) as playing a central role in the neural adaptations to and reinstatement of repeated cocaine administration. In particular, preclinical work by Kalivas and colleagues has advanced a compelling model whereby dysregulated subcortical (i.e., nucleus accumbens or NAcc) GLU transmission accounts for the vulnerability to reinstated drug seeking in animals. The relevance of this GLU homeostasis hypothesis [14] for CD humans remains largely untested, however, due to the lack of clinical- translational tools capable of measuring GLU levels in the ventral striatum (VS) in humans. Innovations in high-field (7 Tesla), proton magnetic resonance spectroscopy (1H-MRS) by members of our research group now suggest the feasibility of obtaining direct measures of brain GLU in human VS. Thus, the current Exploratory/Developmental R21 application seeks to adapt and apply these advances to the development of a robust, practical, cost-effective, and objective biomarker of dysregulated GLU homeostasis in humans, one that can directly and efficiently inform the evaluation of candidate medications for CD patients. If achieved, the current study would set the stage for future prospective, controlled, biomarker-guided evaluations of candidate pharmacotherapies targeted at restoring GLU homeostasis on both a population, and even personalized medicine basis.