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，特别是在可卡因寻求行为中的丘脑核中的谷氨酸神经传递的关键作用。本实验将研究一种新的谷氨酸来源，特别是从胱氨酸谷氨酸反向转运蛋白释放的非囊泡谷氨酸对可卡因的行为和神经化学作用的贡献。这些研究将测试可卡因诱导的致病性神经可塑性包括胱氨酸-谷氨酸反向转运蛋白的适应性的主要假设，靶向这些适应性代表了治疗成瘾的新方法。第一个目标的实验将确定从胱氨酸-谷氨酸反向转运蛋白释放的谷氨酸是否通过刺激第2/3组代谢型谷氨酸受体来阻断可卡因的恢复。这可能会通过阻止可卡因诱导的细胞外谷氨酸和多巴胺升高来阻止可卡因复吸，其他人已经证明这对可卡因复吸至关重要。为此，将检查组2/3 mGluR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。第二个目标的实验将研究可卡因诱导的可塑性是否涉及胱氨酸-谷氨酸反向转运蛋白出现在自我管理或撤回的过程中，以及这些适应是否对差异可卡因摄入量敏感。 此外，这些实验将检查可卡因摄入量和戒断时间是否会产生可卡因恢复和可卡因诱导的涉及胱氨酸-谷氨酸反向转运蛋白的可塑性的平行变化。最后，最后一组实验将利用更临床相关的程序来检查半胱氨酸前药N-乙酰半胱氨酸的推定的抗渴望功效。具体而言，这些实验将检查长期给予N-乙酰半胱氨酸逆转可卡因的神经化学和行为效应的能力。这是这个建议的目标，揭示胱氨酸-谷氨酸反向转运蛋白作为一个新的目标，潜在的药物治疗可卡因成瘾。此外，这些实验也有可能说明胱氨酸-谷氨酸反向转运蛋白的谷氨酸非囊泡释放是正常和患病状态下谷氨酸神经传递的基本组成部分，鉴于涉及谷氨酸的疾病数量，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.