Targeting System Xc- for the Treatment of Addiction

对可卡因和其他非法药物的依赖估计给我们的社会造成了1810亿美元的损失 这相当于每个美国公民603美元。上瘾的代价可以大大降低。 通过使用治疗；不幸的是，包括可卡因在内的许多滥用药物缺乏 单一批准的药物疗法。对可卡因等精神运动兴奋剂的上瘾 以毒品消费的转变为特点的，从休闲、娱乐的使用方式转变为更 由于药物引起的大脑变化而产生的强迫的、过度的模式 功能正常。为了开发有效的治疗方法，很可能有必要确定 并针对潜在的成瘾改变的大脑功能。为此，毒品引发的 半胱氨酸-谷氨酸逆向转运体释放谷氨酸的变化与 神经传递的病理改变与半胱氨酸-谷氨酸交换的正常化 在临床前模型中阻止强迫寻求药物。进一步的，小规模的临床研究 使用乙酰半胱氨酸来靶向半胱氨酸-谷氨酸交换已显示出适度的效果 包括减少对毒品的渴望和可卡因的使用。N-乙酰半胱氨酸的疗效有限 由于肝脏的广泛新陈代谢和向大脑的被动运输能力差。结果, 目前的提议寻求开发新的化学实体，这些化学实体更有效和 有效地靶向大脑中的半胱氨酸-谷氨酸交换。目标1将涉及设计 32-40种化合物。AIM 2将利用体外和体内筛选技术 确定哪些化合物在靶向胱氨酸-谷氨酸方面最有效和最有效 交换。具体地说，我们将使用纯胶质皮质培养来确定 脑细胞利用新的配体来靶向胱氨酸-谷氨酸交换。接下来，我们将 通过评估这些配体的能力来筛选体内最有希望的化合物 绕过肝脏代谢，进入大脑，靶向半胱氨酸-谷氨酸逆向转运体。目标 3将确定这些新化合物在阻断可卡因普利的效力和疗效， 应激启动和可卡因配对提示启动的可卡因寻找 强迫性寻药的临床前模型。总体而言，这些实验具有 将半胱氨酸-谷氨酸逆向转运蛋白确定为治疗骨肉瘤的新靶点的可能性 并产生一系列可能最终有效治疗的化合物 可卡因成瘾。

Addiction to cocaine and other illicit drugs is estimated to cost our society $181 billion which equates to $603 per U.S. citizen. The cost of addiction can be dramatically lowered through the use of treatments; unfortunately, many drugs of abuse, including cocaine, lack a single approved pharmacotherapy. Addiction to psychomotor stimulants, such as cocaine, is marked by a transition in drug consumption from a casual, recreational style of use to a more compulsive, excessive pattern that arises as a result of drug-induced changes in brain functioning. In order to develop effective treatments, it will likely be necessary to identify and target altered brain functioning underlying addiction. Towards this end, drug-induced changes in glutamate release from cystine-glutamate antiporters have been linked to pathological alterations in neural transmission and normalizing cystine-glutamate exchange blocks compulsive drug-seeking in preclinical models. Further, small-scale clinical studies using acetylcysteine to target cystine-glutamate exchange have shown modest efficacy including reduced drug craving and cocaine use. The efficacy of N-acetyl cysteine is limited due to extensive metabolism in the liver and poor passive transport into the brain. As a result, the present proposal seeks to develop novel chemical entities that are more potent and effective in targeting cystine-glutamate exchange in the brain. Aim 1 will involve the design of 32-40 compounds. Aim 2 will utilize in vitro and in vivo screening techniques to determine which compounds are most effective and potent in targeting cystine-glutamate exchange. Specifically, we will use pure glial cortical cultures to determine the capacity of brain cells to utilize the novel ligands to target cystine-glutamate exchange. Next, we will screen the most promising compounds in vivo by assessing the capacity of these ligands to bypass hepatic metabolism, enter into the brain, and target cystine-glutamate antiporters. Aim 3 will determine the potency and efficacy of these novel compounds in blocking cocaineprimed, stress-primed, and cocaine-paired cue primed reinstatement of cocaine-seeking in preclinical models of compulsive drug seeking. Collectively, these experiments have the potential to identify cystine-glutamate antiporters as a novel target in the treatment of addiction and to generate a series of compounds that may ultimately be effective in treating cocaine addiction.