Chronic Adaptations in Glutamatergic and Dopaminergic Signaling in Nicotine Abuse

描述（由申请人提供）：吸烟是导致过早死亡的主要原因。尼古丁，烟草中的主要活性生物碱，被普遍认为是维持吸烟行为的原因。此外，长期使用成瘾性药物已被发现在涉及学习和行为可塑性的皮质纹状体脑回路中产生持久的神经适应。现有证据表明，NA内谷氨酸稳态（突触外和突触神经元谷氨酸浓度之间的平衡，调节突触可塑性）的破坏是导致这种慢性复发易感的机制。据认为，在这一途径中，药物引起的动态变化损害了有助于动机行为适应性调节的正常信息处理。然而，目前尚不清楚尼古丁自我给药和尼古丁寻求行为的恢复在多大程度上导致谷氨酸稳态的改变。我建议使用尼古丁寻求的动物模型来确定尼古丁戒断和恢复尼古丁寻求期间谷氨酸稳态的变化是否与可卡因戒断和可卡因寻求期间发生的变化相似。具体来说，我假设尼古丁自我给药会改变与谷氨酸稳态相关的蛋白质水平，以及在线索诱导的恢复过程中突触释放NA谷氨酸和多巴胺。拟议的研究将确定尼古丁和可卡因之间的关系，如果有的话，作为不同药物滥用复发的潜在神经生物学机制的谷氨酸稳态的改变。同时，这项研究也有可能揭示尼古丁成瘾的新机制，从而有助于制定更有效的药物治疗方案。在此过程中，我将接受Western blot分析、尼古丁自我给药后无净通量的体内微透析和消失训练，以及cu诱导大鼠尼古丁寻求行为的恢复。

DESCRIPTION (provided by applicant): Tobacco smoking is a leading cause of premature death. Nicotine, the primary active alkaloid in tobacco, is generally accepted as being responsible for maintaining smoking behavior. As well, chronic use of addictive drugs has been found to produce enduring neuroadaptations in the corticostriatal brain circuitry involved in the plasticity of learning and behavior. Existing evidence suggests that a disruption in glutamate homeostasis (a balance between extrasynaptic and synaptic neuronal glutamate concentrations that regulate synaptic plasticity) within the NA is a contributing mechanism to this chronic relapse vulnerability. It is thought that dynamic drug-induced changes in this pathway impair the normal processing of information that contributes to the adaptive regulation of motivated behavior. It is unclear, however, to what extent nicotine self-administration and the reinstatement of nicotine-seeking behavior causes alterations in glutamate homeostasis. I am proposing to use an animal model of nicotine-seeking to determine if changes in glutamate homeostasis during nicotine withdrawal and reinstated nicotine-seeking are similar to those that occur during cocaine withdrawal and cocaine-seeking. Specifically, I hypothesize that nicotine self-administration will change protein levels associated with glutamate homeostasis, as well as synaptic release of NA glutamate and dopamine during cue-induced reinstatement. The proposed research will determine the relationship, if any, between nicotine and cocaine on alterations in glutamate homeostasis as an underlying neurobiological mechanism of relapse to different drugs of abuse. As well, the proposed research has the potential to reveal novel mechanisms of nicotine addiction, and thus may aid in targeting more effective pharmacological treatment. In the process, I will be trained in Western blot analysis, in vivo microdialysis involving no-net flux following nicotine self-administration and extinction training, as well as cu-induced reinstatement of nicotine-seeking behavior in rats. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability, even after extended drug abstinence. The proposed research has the potential to reveal novel neurobiological mechanisms of nicotine addiction, and could contribute to the development of novel therapeutic options aimed at reversing nicotine- induced alterations.