Glutamate-Glutamine Cycling (Vcyc) in Cocaine Abstinence using 13C-MRS

使用 13C-MRS 进行可卡因戒断中的谷氨酸-谷氨酰胺循环 (Vcyc)

• 批准号: 8861373
• 负责人: ROBERT T MALISON
• 金额: $ 45.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8861373
• 关键词: Abstinence; Accounting; Acetylcysteine; Basic Science; Behavior; Biological Markers; Brain; Ceftriaxone; Cell Respiration; Cerebrum; Chronic; Clinical; Clinical Management; Clinical Treatment; Clinical Trials; Cocaine; Cocaine Dependence; Compulsive Behavior; Coupling; Cues; Cysteine; Data; Development; Dose; Evaluation; Functional disorder; Funding; Future; Glucose; Glutamates; Glutamine; Homeostasis; Human; Investigation; Label; Laboratory Animals; Lead; Light; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Methods; Mitochondria; Molecular; Neurobiology; Neurocognitive Deficit; Neurotransmitters; Pentoxifylline; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Proteins; Relapse; Research; Rest; Riluzole; Risk; Seminal; Staging; Testing; Time; Up-Regulation; base; cocaine relapse prevention; comparative efficacy; cost; drug abstinence; experience; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; metabolic rate; neurotransmission; oxidation; pre-clinical; prevent; prospective; public health relevance; transmission process

 DESCRIPTION (provided by applicant): 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. Two decades ago, seminal studies in chronic cocaine abusers (Volkow 1992, 1993) identified resting- state reductions in prefrontal cortical (PFC) glucose metabolism (as measured by [18F]-FDG PET) during states of sustained drug abstinence (> 1 week and up to 3 months). These deficits in neuroenergetics are believed to account for the neurocognitive impairments that underlie the impulsive actions, compulsive behaviors, and risky decisions that lead to relapse in cocaine addicts. Despite their clinical importance, the molecular basis of these deficits is still unknown today. The current exploratory-developmental R01 seeks to directly test whether deficits in PFC glucose metabolism are reflective of abnormal glutamate neurotransmission in light of: 1) data demonstrating the direct neurometabolic coupling of cortical glucose metabolism and glutamatergic neurotransmission (Belanger 2011); 2) the unique ability of isotopic ([13C]-glucose) magnetic resonance spectroscopy (13C- MRS) to simultaneously and noninvasively assess neuroenergetics (mitochondrial glucose oxidation or VTCA) and glutamatergic neurotransmission (glutamate-glutamine cycling or VCYC) in humans (Rothman 2011), and 3) preclinical evidence demonstrating the importance of dysregulated glutamate homeostasis in cocaine- and cue-induced reinstatement of drug-seeking (Kalivas 2009). If confirmed, the current study would set the stage for future prospective, controlled, biomarker-guided (VCYC) evaluations of candidate pharmacotherapies (e.g., N-acetylcysteine, ceftriaxone, riluzole and/or pentoxifylline) targeted at restoring glutamate homeostasis (i.e., based on up-regulation of glial proteins, such as GLT-1, that mediate glutamate cycling / neurometabolic coupling).

 描述（由申请人提供）：复发仍然是可卡因成瘾治疗中一个关键的未解决的挑战。虽然许多人会成功地开始戒断，但绝大多数可卡因滥用者在患病期间会经历多次复发，许多人将无法实现持久的无毒品生活。因此，目前缺乏减少复发风险的药物仍然是可卡因依赖临床管理的一个主要差距。20年前，在慢性可卡因滥用者中进行的开创性研究（Escherow 1992，1993）确定了在持续药物戒断状态（> 1周和长达3个月）期间前额叶皮质（PFC）葡萄糖代谢的静息状态降低（通过[18F]-FDG PET测量）。这些神经能量学的缺陷被认为是导致可卡因成瘾者冲动行为、强迫行为和冒险决定的神经认知障碍的原因。尽管它们在临床上很重要，但它们的分子基础 赤字至今仍是未知数。目前的探索-发展R 01旨在直接测试PFC葡萄糖代谢缺陷是否反映了异常谷氨酸神经传递，其依据是：1）数据表明皮质葡萄糖代谢和谷氨酸能神经传递的直接神经代谢偶联（Belanger 2011）; 2）同位素的独特能力[13 C]-葡萄糖磁共振波谱（13 C- MRS）同时和非侵入性评估神经能量学（线粒体葡萄糖氧化或VTCA）和谷氨酸能神经传递（谷氨酸-谷氨酰胺循环或VCYC）（Rothman 2011），和3）临床前证据表明谷氨酸稳态失调在可卡因和线索诱导的药物寻求恢复中的重要性（Kalivas 2009）。如果得到证实，目前的研究将为未来对候选药物治疗（例如，N-乙酰半胱氨酸、头孢曲松、利鲁唑和/或戊酰茶碱），其靶向恢复谷氨酸体内平衡（即，基于介导谷氨酸循环/神经代谢偶联的神经胶质蛋白如GLT-1的上调）。