Noradrenergic modualtion of Glutamate Transmission in Prefrontal Cortex--Cocaine

去甲肾上腺素（NE）调节谷氨酸介导的许多脑区兴奋。在前额叶皮层，谷氨酸与可卡因的一些长期影响密切相关，如致敏；一种持续的行为，类似于惊恐发作、焦虑和最终的偏执型精神病。Jimenez-Rivera et 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 -去甲肾上腺素能受体。来自Ortiz等人的初步证据表明，在缺乏NE的可卡因处理大鼠的突触体中，谷氨酸摄取增加。另一方面，Ulrich等人（1998）发现了可以被可卡因取代的RNA适配体，并提出了使用这些适配体作为可卡因致敏的摄取抑制剂和调节剂的独特机会。可卡因抑制多巴胺（DA）和去甲肾上腺素的再摄取，其效力非常相似。本项目拟开展的合作研究重点是阐明NE对PFC中谷氨酸传递的神经调节作用，以及该作用如何被可卡因修饰。前额叶皮层中NE对谷氨酸能张力的神经调节对可卡因的一些长期影响（致敏）的发展至关重要。这一假设将通过药理学改变PFC的NE输入来验证，同时监测谷氨酸传递的神经化学变化。与此同时，将测试干扰DA和NE摄取的RNA适体是否能够干扰NE对pfc中谷氨酸传递的调节作用。该项目是CMBN长期相互作用的直接结果。在过去的三年里，中加勒比大学的Jimenez- Rivera博士和波多黎各大学的Ortiz博士一直在与康奈尔大学的Hess博士进行交流。申请者将专注于研究NE对可卡因处理大鼠PFC中谷氨酰胺能张力调节的行为、电生理和神经化学改变。另一方面，合作者将合成和筛选具有定义特征的RNA适体(即。可卡因可替代性等)。提出的实验方案最大限度地利用了这两个组成部分的专业知识，并与理解神经适应性变化的趋同努力相一致。这种合作为两个机构的参与者提供了进一步的理论和实践方法的机会，Ulrich等人1998年的工作就是例证。所提出的实验结果对于理解NE如何调节pfc中的谷氨酸神经传递至关重要。可卡因，RNA适配体)应该揭示NE调节作用的相关性，并提供新的治疗策略。

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.