Cystine-Glutamate Antiporters and Cocaine Reinstatement

对成瘾神经基础的研究表明，谷氨酸在神经传递中起着关键作用。 尤其是在伏隔核，在寻找可卡因的行为中。本提案中的实验将 研究一种新的谷氨酸来源的贡献，特别是来自胱氨酸的非囊泡性谷氨酸释放。 谷氨酸逆向转运体，对可卡因的行为和神经化学影响。这些研究将测试主要的 假设可卡因诱导的致病神经可塑性包括半胱氨酸-谷氨酸逆向转运体的适应，以及 以这些适应为目标是治疗成瘾的一种新方法。第一个目标的实验将 确定从半胱氨酸-谷氨酸逆向转运体释放的谷氨酸是否通过刺激阻止可卡因的恢复 第2/3组代谢型谷氨酸受体。这可能会阻止可卡因的恢复- 诱导细胞外谷氨酸和多巴胺的升高，这已被其他人证明是可卡因的关键 复职。为此，2/3组mGluR拮抗剂阻断N-乙酰半胱氨酸调节的能力 可卡因诱导的细胞外谷氨酸升高和恢复的情况将被研究。在中国的实验 第二个目标将检查可卡因诱导的可塑性是否涉及半胱氨酸-谷氨酸逆向转运体。 自我给药或戒断的过程，以及这些适应对不同的可卡因摄入量是否敏感。 此外，这些实验还将检验可卡因的摄入量和戒断时间是否会产生平行的变化 在可卡因恢复和可卡因诱导的可塑性中，涉及半胱氨酸-谷氨酸逆向转运体。最后，最后一组 实验将利用一种更具临床相关性的程序来检查假定的抗渴求功效 半胱氨酸前体药物N-乙酰半胱氨酸。具体地说，这些实验将检验慢性给药的能力。 N-乙酰半胱氨酸可以逆转可卡因的神经化学和行为效应。这项提议的目标是 揭示胱氨酸-谷氨酸逆向转运体作为治疗可卡因成瘾的潜在药物治疗的新靶点。此外， 这些实验也有可能说明胱氨酸-谷氨酸对谷氨酸的非囊泡释放。 在正常和疾病状态下，逆向转运蛋白都是谷氨酸神经传递的基本成分，这是 考虑到涉及谷氨酸的疾病的数量，这将产生深远的影响。

Attempts to identify the neural basis of addiction have demonstrated a critical role for glutamate neurotransmission, particularly in the nucleus accumbens, in cocaine-seeking behavior. The experiments in the present proposal will examine the contribution of a novel source of glutamate, specifically nonvesicular glutamate release from cystine- glutamate antiporters, to the behavioral and neurochemical effects of cocaine. These studies will test the primary hypothesis that cocaine-induced pathogenic neuroplasticity includes adaptations in cystine-glutamate antiporters, and targeting these adaptations represents a novel approach in treating addiction. Experiments in the first aim will determine whether glutamate released from cystine-glutamate antiporters blocks cocaine reinstatement by stimulating group 2/3 metabotropic glutamate receptors. This could potentially block cocaine reinstatement by preventing cocaine- induced elevations in extracellular glutamate and dopamine, which have been shown by others to be critical for cocaine reinstatement. Toward this end, the capacity of the group 2/3 mGluR antagonist to block N-acetylcysteine regulation of cocaine-induced elevations in extracellular glutamate and reinstatement will be examined. Experiments in the second aim will examine whether cocaine-induced plasticity involving cystine-glutamate antiporters emerges during the course of self-administration or withdrawal and whether these adaptations are sensitive to differential cocaine intake. In addition, these experiments will examine whether cocaine intake and length of withdrawal produce parallel changes in cocaine reinstatement and cocaine-induced plasticity involving cystine-glutamate antiporters. Finally, the last set of experiments will utilize a more clinically relevant procedure to examine the putative anti-craving efficacy of the cysteine prodrug N-acetylcysteine. Specifically, these experiments will examine the capacity of chronic administration of N-acetylcysteine to reverse the neurochemical and behavioral effects of cocaine. It is the goal of this proposal to reveal cystine-glutamate antiporters as a novel target for potential pharmacotherapies for cocaine addiction. Moreover, these experiments also have the potential to illustrate that nonvesicular release of glutamate by cystine-glutamate antiporters is a fundamental component of glutamate neurotransmission in both the normal and diseased states, which would have far reaching implications given the number of disorders that involve glutamate.