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，特别是在伏隔核中，在可卡因寻求行为中起关键作用。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转运体中释放的非囊状谷氨酸，对可卡因的行为和神经化学作用的贡献。这些研究将验证可卡因诱导的致病性神经可塑性包括胱氨酸-谷氨酸反转运蛋白的适应性的主要假设，并且针对这些适应性代表了一种治疗成瘾的新方法。第一个目标的实验将确定从胱氨酸-谷氨酸反转运蛋白释放的谷氨酸是否通过刺激2/3组代谢性谷氨酸受体来阻止可卡因恢复。这可能通过防止可卡因引起的细胞外谷氨酸和多巴胺的升高来潜在地阻止可卡因的恢复，这已经被其他人证明是可卡因恢复的关键。为此，将研究2/3组mGluR拮抗剂阻断n -乙酰半胱氨酸调节可卡因诱导的细胞外谷氨酸升高和恢复的能力。第二个目标的实验将检验可卡因诱导的可塑性是否包括胱氨酸-谷氨酸反转运蛋白在自我给药或戒断过程中出现，以及这些适应性是否对不同的可卡因摄入量敏感。

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.