Noradrenergic modualtion of Glutamate Transmission in Prefrontal Cortex--Cocaine

去甲肾上腺素(NE)在许多脑区调节谷氨酸介导的兴奋。在前额叶皮质，谷氨酸与可卡因的一些长期影响密切相关，如敏化；一种类似于恐慌症发作、焦虑和最终偏执型精神病的持续性行为。希门尼斯-里维拉等人。1998年(抽象7TB PR神经科学会议)表明，可卡因的一些长期影响需要激活去甲肾上腺素能受体。来自Ortiz等人的初步证据表明，去甲肾上腺素耗竭的可卡因治疗大鼠的突触体内谷氨酸摄取增加。另一方面，Ulrich et al.(1998)已经确定了可以被可卡因取代的RNA适配子，并提供了将这些适配子用作可卡因敏化的可能摄取抑制剂和修饰剂的独特机会。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。本项目中提出的合作研究重点是阐明NE在PFC中对谷氨酸传递的神经调制作用以及可卡因如何改变这一作用。去甲肾上腺素对前额叶皮质谷氨酸能张力的神经调节对于可卡因的一些长期效应(敏化)的发展至关重要。这一假说将通过药理学改变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。同时，可以干扰DA和NE摄取的RNA适配子将被测试它们是否有能力干扰NE对PFC中谷氨酸传递的调制作用。这个项目是CMBN长期互动的直接结果。中央加勒比大学的希门尼斯-里维拉博士和奥尔蒂斯博士(大学)一直在与康奈尔大学的赫斯博士交流。在过去三年里。申请者将专注于去甲肾上腺素对可卡因处理大鼠前额叶皮质谷氨酸能张力调节的行为、电生理和神经化学修饰。另一方面，合作者将合成并筛选具有定义特征的RNA适配子(即，可卡因的可替换性等)。提出的实验方案最大限度地发挥了这两个部分的专业知识，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机会，以促进他们的理论和实践方法，Ulrich等人1998年的工作就是一个例证。这些实验的结果对于理解去甲肾上腺素如何调节前额叶谷氨酸神经传递至关重要。药理操作(即可卡因、RNA适配子)应揭示去甲肾上腺素调节作用的相关性(S)，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.