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）调节许多大脑区域的谷氨酸介导的激发。在前额叶皮质中，谷氨酸与可卡因的某些长期作用（例如敏化）有着强烈的影响。持续的行为类似于惊恐发作，焦虑和最终偏执的精神病。 Jimenez-Rivera等。 AL 1998（摘要7TB PR神经科学会议）表明，可卡因的一些长期影响需要激活α甲肾上腺素能受体。 Ortiz等人的初步证据表明，来自可卡因治疗的大鼠的突触体增加了谷氨酸的摄取，而NE耗尽了。另一方面，Ulrich等人。 （1998年）已经确定了可以通过可卡因替换的RNA适体，并提出了将这些适体的独特机会作为可卡因敏化的摄取抑制剂和修饰符。可卡因抑制具有非常相似的效力的多巴胺（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在PFC中NE对谷氨酸传播的神经调节作用以及可卡因如何修饰该作用。 NE在前额叶皮层中对谷氨酸能张力的神经调节对于开发可卡因的某些长期作用（敏化）至关重要。该假设将通过在监测谷氨酸传播的神经化学变化的同时，通过在药理上改变NE输入来检验。同时，将测试可能干扰DA和NE摄取的RNA适体，以研究其干扰NE对PFC中谷氨酸透射的调节作用的能力。该项目是CMBN长期互动的直接结果。在过去的三年中，中央德尔加勒比大学和奥尔蒂斯大学（波多黎各大学）的Jimenez-Rivera博士一直与Hess（Cornell Univ。）互动。申请人将关注可卡因治疗大鼠PFC中G1utamatergic NE调制的行为，电生理和神经化学修饰。另一方面，合作者将合成具有定义特征的RNA适体（即可卡因位移性等）。实验方案提出的是最大化组件的专业知识，并且与理解神经适应性变化的收敛努力一致。这项合作为两个机构的参与者提供了进一步的机会，以进一步以乌尔里希（Ulrich）等人的工作为例，1998年。拟议的实验的结果对于理解NE如何调节PFC中的谷氨酸神经传递至关重要。药理学操纵（即可卡因，RNA适体）应揭示NE调节作用的相关性，并提供新颖的治疗策略。