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

使用 7T 1H-MRS 评估可卡因成瘾中的谷氨酸稳态

基本信息

批准号：
9560713
负责人：
GUSTAVO Adolfo ANGARITA
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9560713
关键词：
Abstinence Acetylcysteine Animals Basic Science Behavior Biological Markers Brain Brain region Clinical Clinical Management Clinical Treatment Cocaine Cocaine Dependence Controlled Study Corpus striatum structure Development Disease Dose Double-Blind Method Evaluation Functional disorder Funding Future Glutamates Homeostasis Human Laboratory Animals Magnetic Resonance Spectroscopy Measures Methods Modeling Neurobiology Neurotransmitters Nucleus Accumbens Patients Pharmaceutical Preparations Pharmacotherapy Placebos Play Population Pre-Clinical Model Protons Randomized Relapse Research Role Scanning Study Subject Testing Time Ventral Striatum Work cocaine relapse prevention cost effective design experience in vivo innovation member neuroadaptation personalized medicine pre-clinical prevent prospective relapse risk tool transmission process

项目摘要

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.

项目概要复发仍然是可卡因成瘾治疗中尚未解决的关键挑战。虽然许多人会成功开始戒毒后，绝大多数可卡因滥用者会在戒毒过程中经历多次复发他们的疾病，许多人将无法实现持久的无毒品生活。因此，目前缺乏药物降低复发风险仍然是可卡因依赖临床管理的一个主要差距。大量基础研究表明谷氨酸 (GLU) 在神经适应中发挥着核心作用并恢复重复使用可卡因。特别是 Kalivas 及其同事的临床前工作提出了一个令人信服的模型，其中皮层下（即伏隔核或 NAcc）GLU 失调传播是动物重新恢复吸毒的脆弱性的原因。此 GLU 的相关性然而，由于缺乏临床证据，CD 人类的稳态假说 [14] 在很大程度上仍未得到检验。能够测量人类腹侧纹状体 (VS) GLU 水平的转化工具。我们的成员在高场 (7 Tesla)、质子磁共振波谱 (1H-MRS) 方面的创新研究小组现在提出了直接测量人类 VS 中脑 GLU 的可行性。因此，当前的探索性/开发性 R21 应用程序旨在将这些进步应用于开发一种稳健、实用、具有成本效益且客观的 GLU 稳态失调生物标志物人类，可以直接有效地为 CD 患者的候选药物评估提供信息。如果实现的话，当前的研究将为未来的前瞻性、受控、生物标志物引导的研究奠定基础评估旨在恢复人群 GLU 稳态的候选药物疗法，以及甚至个性化医疗基础。