Noradrenergic modualtion of Glutamate Transmission in Prefrontal Cortex--Cocaine

前额皮质谷氨酸传输的去甲肾上腺素能调节——可卡因

• 批准号: 6666476
• 负责人: CARLOS A JIMENEZ-RIVERA
• 金额: $ 14.82万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666476
• 关键词: RNA; autoradiography; behavioral habituation /sensitization; chemosensitizing agent; cocaine; cooperative study; glutamate receptor; glutamates; laboratory rat; microinjections; minority institution research support; neural transmission; neuropharmacology; neurotransmitter receptor; norepinephrine; oligonucleotides; prefrontal lobe /cortex

Norepinephrine (NE) modulates glutamate-mediated excitation in many brain areas. In the prefrontal cortex, glutamate is strongly implicated in some of the long-term effects of cocaine such as sensitization; a persistent behavior similar to panic attack, anxiety and eventually paranoid psychosis. Jimenez-Rivera et. al 1998 (Abstract 7tb PR Neuroscience Conference) have shown that some of the long term effects of cocaine requires activation of alpha noradrenergic receptors. Preliminary evidence from Ortiz et al., suggests that glutamate uptake is increased in synaptosomes from cocaine-treated rats depleted of NE. On the other hand, Ulrich et al. (1998) have identified RNA aptamers that can be displaced by cocaine and presents the unique opportunity of using these aptamers as possible uptake inhibitors and modifiers of cocaine sensitization. Cocaine inhibits the reuptake of dopamine (DA) and norepinephrine with very similar potency. The collaborative research proposed in this project is focused on clarifying the neuromodulatory role of NE on glutamate transmission in the PFC and how this role is modified by cocaine. Neuromodulation of glutamatergic tone by NE in the prefrontal cortex is critical for the development of some of the long-term effects of cocaine (sensitization). This hypothesis will be tested by pharmacologically altering NE input in the PFC, while monitoring the neurochemical changes in glutamate transmission. In parallel, RNA aptamers that could interfere with DA and NE uptake will be tested for their ability to interfere with the modulatory effects of NE on glutamate transmission in the PFC. This project is the direct result of CMBN's long-term interactions. Dr. Jimenez- Rivera at Universidad Central del Caribe and Dr. Ortiz (Univ. of Puerto Rico) have been interacting with Dr. Hess (Cornell Univ.) for the past three years. The applicants will focus on the behavioral, electrophysiological and neurochemical modifications of NE modulation of g1utamatergic tone in the PFC of cocaine-treated rats. On the other hand, the collaborators will synthesize and screen for RNA aptamers with defined characteristics (ie. cocaine displaceability, among others). The experimental scheme proposed maximizes the expertise of both components and is consistent with a convergent effort towards understanding neuroadaptive changes. This collaboration provides the opportunity for participants at both institutions to further their theoretical and practical approaches exemplified by the work of Ulrich et al., 1998. The results of the proposed experiments are crucial for understanding how NE modulates glutamate neurotransmission in the PFC. Pharmacological manipulations (ie. Cocaine, RNA aptamers) should reveal the relevance of NE modulatory role(s) as well as, provide novel therapeutic strategies.

去甲肾上腺素（NE）调节许多脑区中谷氨酸介导的兴奋。在前额叶皮层，谷氨酸与可卡因的一些长期影响密切相关，例如致敏;一种类似于恐慌发作，焦虑和最终偏执性精神病的持续行为。希门尼斯-里韦拉等等人1998（Abstract 7 tb PR Neuroscience Conference）已经表明可卡因的一些长期作用需要α去甲肾上腺素能受体的激活。Ortiz等人的初步证据，表明可卡因处理的NE耗竭大鼠的突触体中谷氨酸摄取增加。另一方面，Ulrich等人（1998年）已经鉴定出可被可卡因置换的RNA适体，并提供了使用这些适体作为可卡因致敏的可能的摄取抑制剂和修饰剂的独特机会。可卡因以非常相似的效力抑制多巴胺（DA）和去甲肾上腺素的再摄取。该项目中提出的合作研究的重点是阐明NE对PFC中谷氨酸传递的神经调节作用以及可卡因如何改变这种作用。前额叶皮质中NE对谷氨酸能张力的神经调节对于可卡因的一些长期效应（致敏）的发展至关重要。这一假设将通过改变PFC中的NE输入来检验，同时监测谷氨酸传递中的神经化学变化。与此同时，RNA适体，可以干扰DA和NE的摄取将被测试他们的能力，干扰NE对谷氨酸传输的PFC的调制作用。这个项目是CMBN的长期相互作用的直接结果。加勒比中央大学的希门尼斯-里维拉博士和奥尔蒂斯博士（波多黎各大学）一直在与赫斯博士（康奈尔大学）互动。一直在做申请人将关注可卡因处理的大鼠PFC中谷氨酸能紧张的NE调节的行为、电生理和神经化学修饰。另一方面，合作者将合成和筛选具有确定特征的RNA适体（即。 可卡因的可吸收性等）。提出的实验方案最大限度地提高了这两个组件的专业知识，是一致的收敛努力，了解神经适应性的变化。这种合作为这两个机构的参与者提供了机会，以进一步推进他们的理论和实践方法，例如乌尔里希等人的工作，1998.所提出的实验的结果是至关重要的了解NE如何调节谷氨酸在PFC的神经传递。RNA适体）应该揭示NE调节作用的相关性以及提供新的治疗策略。