Glutamate Signaling and Drug Abuse

谷氨酸信号传导和药物滥用

• 批准号: 6868951
• 负责人: MOHAMMADHOSSEIN BEHNAM GHASEMZADEH
• 金额: $ 21.75万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868951
• 关键词: AMPA receptors; behavior test; behavioral habituation /sensitization; binding proteins; biological signal transduction; cell membrane; cocaine; dopamine; drug abuse; drug addiction; glutamate receptor; glutamates; histology; immunoprecipitation; intracellular; laboratory rat; neural transmission; nucleus accumbens; phosphorylation; posttranslational modifications; prefrontal lobe /cortex; protein transport; synapses; tegmentum; western blottings

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.

描述（由申请人提供）：滥用苯丙胺类药物 精神兴奋剂是全世界的一个医学和社会问题。这 这些药物的有益特性与其增加的能力有关 前脑中多巴胺的细胞外浓度，特别是在 伏隔核。支配伏隔核的多巴胺能神经元 起源于腹侧被盖区，该区域已被证明发挥着关键作用 在慢性药物作用的发展中的作用。尽管我们的技术取得了进步 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，多项调查显示，除了 多巴胺能在精神兴奋作用、兴奋性神经传递中的作用 也起着非常关键的作用。谷氨酸是主要的兴奋剂 大脑以及伏隔核和腹侧被盖中的神经递质 该区域接受来自前额皮质的主要谷氨酸能神经支配。这些 研究表明，作用于兴奋性神经传递的药物可能是 治疗精神兴奋剂滥用的有效治疗剂。数据 该提案中提出的建议表明，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并可能发挥作用 重复用药后长期持续的神经适应发挥重要作用 接触。 Homer 蛋白家族是谷氨酸受体结合蛋白之一 特异性结合代谢型谷氨酸受体的蛋白质。这 这些蛋白质在伏隔核中的表达在重复后发生改变 可卡因暴露。此外，在 NA 期间降低这些蛋白质的水平 反复接触可卡因可防止行为的发展 敏化。基于这些结果和其他文献中的一系列 提出实验来研究这些脚手架的功能作用 伏隔核兴奋性传递中的蛋白质及其在药物中的作用 诱导突触可塑性。