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

项目摘要 复发仍然是可卡因成瘾治疗中一个尚未解决的关键挑战。虽然许多人会成功， 开始戒断，绝大多数可卡因滥用者将经历多次复吸的过程中， 他们的疾病，许多人将无法实现持久的无毒品生活。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个主要空白。 大量的基础研究指出谷氨酸（GLU）在神经适应中起着核心作用， 并恢复重复可卡因给药。特别是Kalivas及其同事的临床前工作 已经提出了一个令人信服的模型，其中失调的皮层下（即，神经核或NAcc）GLU 传播是动物重新开始吸毒的原因。该GLU的相关性 然而，由于缺乏临床证据，CD人类的稳态假说[14]在很大程度上尚未得到验证， 翻译工具，能够测量腹侧纹状体（VS）中的GLU水平在人类。 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 一个研究小组现在提出了在人类VS中获得脑GLU的直接测量的可行性。 目前的探索性/开发性R21应用寻求适应和应用这些进展， 开发一种稳健、实用、具有成本效益和客观的GLU稳态失调生物标志物， 人类，一个可以直接和有效地告知候选药物的CD患者的评价。 如果实现，目前的研究将为未来的前瞻性，对照，生物标志物引导的研究奠定基础。 评价候选药物疗法，旨在恢复人群的GLU稳态， 甚至是个性化的医学基础。

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.