Can beta-lactam antibiotics decrease morphine physical dependence?

描述(由申请者提供)：世界上最常用的抗生素能否通过干扰谷氨酸传递来控制吗啡成瘾？最近的证据表明，β-内酰胺类抗生素是唯一能够直接增加中枢神经系统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，这种转运蛋白负责哺乳动物大脑90%的谷氨酸重新摄取。众所周知，GLT-1转运体功能障碍导致细胞外谷氨酸的增加，通过介导吗啡的身体依赖和戒断过程，从而导致吗啡成瘾的持续。因此，控制这种成瘾的一个有希望的方法是用激活GLT-1转运体的药物(例如，β-内酰胺类抗生素)来增加细胞外谷氨酸的清除。为这些抗生素在医学上建立一个新的位置的下一步是确定它们是否真的抑制了清醒动物体内吗啡身体依赖和戒断的行为和神经化学影响。本文提出的实验结果将阐明β-内酰胺类抗生素在吗啡身体依赖的行为和神经化学效应中的作用，并确定抗生素是否会改变吗啡初治和吗啡依赖动物的细胞外谷氨酸水平。有待检验的总体假设是，β-内酰胺类抗生素除了激活GLT-1外，还能减少细胞外谷氨酸，从而防止吗啡身体依赖的形成。将采取多学科的方法来验证这一假设，建议在神经化学和行为层面上进行实验。其具体目的是：(1)确定重复给予β-内酰胺是否能抑制吗啡的身体依赖和戒断；(2)在吗啡依赖和吗啡依赖大鼠中，确定β-内酰胺类抗生素是否减少了脑部已知的介导吗啡依赖的区域中的细胞外谷氨酸。这些研究的综合结果将阐明β-内酰胺类抗生素和谷氨酸能系统之间与阿片成瘾有关的重要相互作用，并描绘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：吗啡身体依赖的部分原因是大脑中谷氨酸能传递的增加。由于β-内酰胺类抗生素是唯一能够直接增加大脑细胞对谷氨酸重新摄取的实用药物，这些广泛使用的药物可能对临床治疗吗啡成瘾有用。这项提议的目的是确定β-内酰胺类抗生素除了增加谷氨酸的重新摄取外，是否还通过干扰谷氨酸能传递来减少大鼠对吗啡的身体依赖。

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.