Cystine-Glutamate Antiporters and Cocaine Reinstatement

试图确定成瘾的神经基础已经证明谷氨酸神经传递的关键作用， 尤其是在可卡因寻找行为的丘脑核中。本提案中的实验将 研究一种新的谷氨酸来源的贡献，特别是从胱氨酸释放的非囊泡谷氨酸， 谷氨酸反向转运蛋白，可卡因的行为和神经化学作用。这些研究将测试主要的 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的假设， 以这些适应为目标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 2/3型代谢型谷氨酸受体。这可能会通过阻止可卡因- 引起细胞外谷氨酸和多巴胺的升高，这已经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 可卡因引起的细胞外谷氨酸盐升高和恢复将被检查。的实验 第二个目标是研究可卡因诱导的涉及胱氨酸-谷氨酸反向转运蛋白的可塑性是否在可卡因诱导的脑损伤过程中出现。 自我给药或戒断过程以及这些适应是否对不同的可卡因摄入量敏感。 此外，这些实验还将检验可卡因摄入量和戒断时间长短是否会产生平行变化 可卡因恢复和可卡因诱导的可塑性，涉及胱氨酸-谷氨酸反向转运蛋白。最后，最后一组 实验将利用更临床相关的程序来检查所述药物的推定的抗渴望功效。 半胱氨酸前药N-乙酰半胱氨酸。具体而言，这些实验将检查慢性给药的能力 N-乙酰半胱氨酸逆转可卡因的神经化学和行为效应。本提案的目的是 揭示胱氨酸-谷氨酸反向转运蛋白作为可卡因成瘾潜在药物疗法的新靶点。此外，委员会认为， 这些实验也有可能说明胱氨酸-谷氨酸非囊泡释放谷氨酸 反向转运蛋白是正常和疾病状态下谷氨酸神经传递的基本成分， 将有深远的影响，因为涉及谷氨酸的疾病数量。

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.