Can beta-lactam antibiotics decrease morphine physical dependence?

描述（由申请人提供）：世界上最常用的抗生素是否可以通过干扰阿片类药物的传递来控制吗啡成瘾？最近的证据表明，β-内酰胺抗生素是唯一能够直接增加CNS中谷氨酸再摄取的实用药物。其机制是GLT-1的表达和活性增加，GLT-1是负责哺乳动物大脑中90%谷氨酸再摄取的转运蛋白。众所周知，GLT-1转运蛋白功能障碍导致细胞外谷氨酸的增加，其通过介导吗啡身体依赖和戒断过程而促成吗啡成瘾的持续。因此，管理这种成瘾的一种有希望的方法是用激活GLT-1转运蛋白的药物增加细胞外谷氨酸的清除（例如，β-内酰胺抗生素）。为这些抗生素在医学上建立一个新的地位，下一步是确定它们是否真的能抑制清醒动物的吗啡身体依赖和戒断的行为和神经化学作用。本文提出的实验结果将阐明β-内酰胺抗生素在吗啡身体依赖的行为和神经化学作用中的作用，并确定抗生素是否改变吗啡初治和吗啡依赖动物的细胞外谷氨酸水平。待检验的总体假设是，β-内酰胺抗生素除了激活GLT-1外，还降低细胞外谷氨酸盐，这可防止吗啡身体依赖的发展。一个多学科的方法将被用来测试这一假设，提出在神经化学和行为水平的实验。具体目标是：（1）确定重复β-内酰胺给药是否抑制吗啡身体依赖和戒断;（2）确定在吗啡初治大鼠和吗啡依赖大鼠中，β-内酰胺抗生素是否降低已知介导吗啡依赖的脑区细胞外谷氨酸。这些研究的综合结果将阐明β-内酰胺类抗生素与阿片类药物成瘾相关的阿片能系统之间的重要相互作用，并描述β-内酰胺类抗生素对吗啡介导的行为的影响。公共卫生相关性：吗啡的身体依赖性部分是通过增加大脑中的多巴胺能传递来介导的。由于β-内酰胺抗生素是唯一能够直接增加大脑中谷氨酸盐的细胞再摄取的实用药物，因此这些广泛使用的药物可能在吗啡成瘾的临床管理中有用。本提案的目的是确定β-内酰胺类抗生素除了增加谷氨酸再摄取外，是否通过破坏谷氨酸能传递来降低大鼠的吗啡身体依赖。

DESCRIPTION (provided by applicant): Can the most commonly used antibiotics in the world manage morphine addiction by disrupting glutamatergic transmission? Recent evidence indicates that beta-lactam antibiotics are the only practical pharmaceuticals capable of directly increasing glutamate reuptake in the CNS. The mechanism is an increase in the expression and activity of GLT-1, the transporter protein responsible for 90% of glutamate reuptake in the mammalian brain. It is well known that GLT-1 transporter malfunction leads to an increase in extracellular glutamate which contributes to the perpetuation of morphine addiction by mediating the processes of morphine physical dependence and withdrawal. Therefore, one promising approach for managing this addiction is to increase the clearance of extracellular glutamate with drugs that activate GLT-1 transporters (e.g., beta-lactam antibiotics). The next step in establishing a new place in medicine for these antibiotics is to determine whether they actually inhibit the behavioral and neurochemical effects of morphine physical dependence and withdrawal in conscious animals. Results from experiments proposed herein will elucidate a role for beta-lactam antibiotics in the behavioral and neurochemical effects of morphine physical dependence and determine whether the antibiotics alter extracellular glutamate levels in morphine-na¿ve and morphine-dependent animals. The overall hypothesis to be tested is that beta-lactam antibiotics, in addition to activating GLT-1, decrease extracellular glutamate which prevents the development of morphine physical dependence. A multi-disciplinary approach will be taken to test this hypothesis with experiments proposed at the neurochemical and behavioral levels. The Specific Aims are: (1) To determine if morphine physical dependence and withdrawal are inhibited by repeated beta-lactam administration and (2) To determine, in morphine-na¿ve and morphine-dependent rats, if beta-lactam antibiotics decrease extracellular glutamate in brain regions that are known to mediate morphine dependence. The combined results from these studies will elucidate important interactions between beta-lactam antibiotics and glutamatergic systems as related to opioid addiction and delineate the effect of beta-lactam antibiotics on morphine-mediated behaviors. The Public Health Relevance: Morphine physical dependence is mediated in part by increased glutamatergic transmission in the brain. Because beta-lactam antibiotics are the only practical pharmaceuticals capable of directly increasing the cellular reuptake of glutamate in the brain, these widely used drugs may be useful in the clinical management of morphine addiction. The goal of this proposal is to determine if beta-lactam antibiotics, in addition to increasing glutamate reuptake, decrease morphine physical dependence in rats by disrupting glutamatergic transmission.