Cystine-Glutamate Antiporters and Cocaine Reinstatement

描述(由申请人提供)：试图确定成瘾的神经基础已经证明谷氨酸神经传递，特别是在伏隔核，在寻找可卡因的行为中起着关键作用。本提案中的实验将考察一种新的谷氨酸来源，特别是来自胱氨酸谷氨酸盐逆向转运体的非囊泡性谷氨酸释放，对可卡因的行为和神经化学效应的贡献。这些研究将检验主要假设，即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，而针对这些适应代表着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2/3代谢性谷氨酸受体来阻止可卡因的恢复。这可能会阻止可卡因诱导的细胞外谷氨酸和多巴胺的升高，这可能会阻止可卡因的恢复，而其他人已经证明，这两个因素对可卡因的恢复至关重要。为此，2/3mGluR组拮抗剂阻断N-乙酰半胱氨酸对可卡因诱导的细胞外谷氨酸升高的调节和恢复的能力将被检测。第二个目的的实验将检查在自我给药或戒断过程中是否出现可卡因诱导的涉及半胱氨酸-谷氨酸逆向转运体的可塑性，以及这些适应是否对不同的可卡因摄入量敏感。 此外，这些实验将检验可卡因摄入量和戒断时间是否会在可卡因恢复和可卡因诱导的涉及半胱氨酸-谷氨酸逆向转运体的可塑性方面产生平行的变化。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验半胱氨酸前体药物N-乙酰半胱氨酸的抗欲功效。具体地说，这些实验将检验长期服用N-乙酰半胱氨酸逆转可卡因的神经化学和行为影响的能力。这项提案的目的是揭示胱氨酸-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，这些实验还有可能说明，胱氨酸-谷氨酸逆向转运蛋白对谷氨酸的非囊性释放是正常和疾病状态下谷氨酸神经传递的基本组成部分，考虑到涉及谷氨酸的疾病的数量，这将具有深远的影响。

DESCRIPTION (provided by applicant): 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 cystineglutamate 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.