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Targeting System Xc- for the Treatment of Addiction

用于治疗成瘾的靶向系统 Xc-

基本信息

批准号：
7737627
负责人：
DAVID A BAKER
金额：
$ 77.39万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

项目摘要

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.

可卡因和其他非法药物成瘾估计给我们的社会造成 1810 亿美元的损失相当于每个美国公民 603 美元。成瘾的成本可以大大降低通过治疗；不幸的是，许多滥用药物，包括可卡因，缺乏单一批准的药物治疗。对精神运动兴奋剂（例如可卡因）成瘾是其特点是毒品消费从休闲、娱乐性的使用方式转变为更加由于药物引起的大脑变化而产生的强迫性、过度模式发挥作用。为了开发有效的治疗方法，可能有必要确定并针对成瘾背后改变的大脑功能。为此，通过药物诱导胱氨酸-谷氨酸逆向转运蛋白释放谷氨酸的变化与神经传递的病理改变和胱氨酸-谷氨酸交换的正常化阻止临床前模型中的强迫性药物寻求。此外，小规模临床研究使用乙酰半胱氨酸靶向胱氨酸-谷氨酸交换已显示出适度的功效包括减少对毒品的渴望和可卡因的使用。 N-乙酰半胱氨酸的功效有限由于肝脏的广泛代谢和进入大脑的被动运输不良。因此，本提案旨在开发更有效和更有效的新型化学实体有效靶向大脑中的胱氨酸-谷氨酸交换。目标1将涉及设计 32-40 种化合物。目标 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。具体来说，我们将使用纯神经胶质皮质培养物来确定脑细胞利用新型配体来靶向胱氨酸-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最有前途的体内化合物绕过肝脏代谢，进入大脑，并靶向胱氨酸-谷氨酸逆向转运蛋白。目的 3 将确定这些新型化合物在阻断可卡因引发剂方面的效力和功效，应激引发的和可卡因配对提示引发的可卡因寻求的恢复强迫性寻药的临床前模型。总的来说，这些实验具有确定胱氨酸-谷氨酸逆向转运蛋白作为治疗的新靶点的潜力并产生一系列最终可能有效治疗成瘾的化合物可卡因成瘾。