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

 描述(由申请人提供)：复发仍然是治疗可卡因成瘾的一个严重的未得到满足的挑战。虽然许多人将成功地开始戒毒，但绝大多数吸食可卡因的人将在他们的疾病过程中多次复发，许多人将无法实现持久的无毒生存。因此，目前缺乏降低复发风险的药物仍然是可卡因依赖临床管理的一个主要缺口。20年前，对慢性可卡因滥用者的开创性研究(Volkow 1992,1993)发现，在持续戒毒状态(&gt；1周和3个月)期间，前额叶皮质(PFC)葡萄糖代谢的静息状态减少(由[18F]-FDG PET测量)。神经能量学的这些缺陷被认为是导致可卡因成瘾者复发的神经认知障碍的原因，这些神经认知障碍是导致可卡因成瘾者冲动行为、强迫行为和高风险决定的基础。尽管它们在临床上很重要，但它们的分子基础 赤字在今天仍是个未知数。目前处于探索开发阶段的R01旨在直接测试PFC糖代谢缺陷是否反映了异常的谷氨酸神经传递(Rothman 2011)，以及1)显示皮质糖代谢和谷氨酸能神经传递的直接神经代谢耦合的数据(Belanger 2011)；2)同位素([13C]-葡萄糖)磁共振波谱(13C-MRS)可同时、非侵入性地评估神经能量学(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)的独特能力(Rothman 2011)，以及3)临床前证据表明，在可卡因和线索诱导的戒毒治疗中，调节谷氨酸稳态失调的重要性(Kalivas 2009)。如果得到证实，目前的研究将为未来对候选药物(例如N-乙酰半胱氨酸、头孢曲松、利鲁唑和/或己酮可可碱)进行前瞻性、受控、生物标记物引导(VCYC)评估奠定基础，这些药物旨在恢复谷氨酸稳态(即基于介导谷氨酸循环/神经代谢偶联的胶质蛋白，如GLT-1的上调)。

 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).