Glutamate Signaling and Drug Abuse

描述（由申请人提供）：苯丙胺类药物滥用 精神兴奋剂是一个世界性的医学和社会问题。的 这些药物的奖励特性与它们增加 细胞外浓度的多巴胺在前脑，特别是在 丘脑核支配延髓核的多巴胺能神经元 起源于腹侧被盖区，该区域已被证明对大脑皮层的活动起着关键作用。 在慢性药物效应发展中的作用。尽管我们的技术进步了， 了解这些药物的细胞和分子作用，有效 安非他明和可卡因成瘾的药物治疗仍然存在 难以捉摸最近，一些调查显示，除 多巴胺能神经兴奋作用，兴奋性神经传递 也起着非常关键的作用。谷氨酸是主要的兴奋性 脑内及中脑核和腹侧被盖的神经递质 该区域接受来自前额皮质的主要脑电能神经支配。这些 研究表明，作用于兴奋性神经传递的药物可能 用于治疗精神兴奋剂滥用的有效治疗剂。数据 这一建议表明，最近发现的蛋白质， 与谷氨酸受体结合可以改变谷氨酸能传递， 在反复用药后持久的神经适应中起重要作用 exposure. Homer家族蛋白是谷氨酸受体结合蛋白之一， 与代谢型谷氨酸受体特异性结合的蛋白质。的 这些蛋白质在丘脑核中的表达在反复的 可卡因暴露此外，降低NA中这些蛋白质的水平， 反复接触可卡因会阻止行为性 致敏基于这些结果和文献中的其他结果， 提出实验来研究这些支架的功能作用 丘脑核兴奋性传递蛋白及其在药物中的作用 诱发突触可塑性。

DESCRIPTION (provided by applicant): The abuse of the amphetamine-like psychostimulants is a medical and social problem throughout the world. The rewarding properties of these drugs are linked to their capacity to increase extracellular concentration of dopamine in the forebrain, notably in the nucleus accumbens. The dopaminergic neurons that innervate nucleus accumbens originate in the ventral tegmental area which has been shown to play a critical role in development of chronic drug effects. Despite the advances in our understanding of cellular and molecular actions of these drugs, effective pharmacological treatments for amphetamine and cocaine addiction remain elusive. More recently, a number of investigations have shown that in addition to dopaminergic role in psychostimulant effects, excitatory neurotransmission also plays a very critical role. Glutamate is the major excitatory neurotransmitter in the brain and both nucleus accumbens and ventral tegmental area receive a major glutamatergic innervation from prefrontal cortex. These studies suggest that drugs acting on excitatory neurotransmission may be effective therapeutic agents for treating psychostimulant abuse. The data presented in this proposal suggest that the recently discovered proteins that bind to glutamate receptors can alter glutamatergic transmission and may play an important role in long lasting neuroadaptations after repeated drug exposure. The Homer family of proteins is one of the glutamate receptor binding proteins that bind specifically to metabotropic glutamate receptors. The expression of these proteins in nucleus accumbens is altered after repeated cocaine exposure. Moreover, reducing the level of these proteins in NA during repeated exposure to cocaine prevents the development of behavioral sensitization. Based on these results and others in literature a series of experiments are proposed to study the functional role of these scaffolding proteins in excitatory transmission in nucleus accumbens and their role in drug induced synaptic plasticity.