Molecular and Behavioral Effects of Nicotine Deprivation

尼古丁奖赏是尼古丁成瘾本质的一个组成部分，然而，吸烟和复发 吸烟的动机通常是为了减轻负面情绪和认知能力的缺陷。 此外，促进吸烟复发的尼古丁戒断症状在最初几天最为明显。 戒烟后，暗示这是研究神经机制的关键时期，这可能有助于 又开始吸烟了。到目前为止，与情绪变化相关的潜在电路和机制(S) 尼古丁剥夺后的加工、学习和记忆还没有阐明。动物模型 尼古丁依赖是研究与尼古丁成瘾相关的分子机制的关键。在……里面 特别是，老鼠是一种易于处理的模型，它允许在分子和 人类研究无法提供的遗传水平。因此，这个项目的总体目标是 用小鼠的新表型来确定尼古丁剥夺的早期影响。具体而言，在 目的1研究尼古丁剥夺对脑刺激奖赏(BSR)和语境效应的影响 学习和工作记忆。我们假设长期服用尼古丁会改变神经过程 潜在的情感、学习和记忆，当长期接触停止时，快感缺乏和缺陷 在学习和记忆中会浮现。为了提高我们开发新的治疗方法的能力 为了治疗尼古丁依赖，重要的是验证我们临床前模型和行为学的使用 临床有效药物的表型。因此，在目标2中，我们将评估系统性的影响 伐伦克林(Chantix)对脑刺激奖赏(BSR)和情境学习的影响 尼古丁剥夺后的工作记忆。因为吸烟者经常报告说，缓解压力是一个激励因素 为了促进持续的吸烟行为，我们将调查压力因素(CRF)在 早期尼古丁缺乏期。因此，在目标3中，我们将描述相关的分子机制 通过评估CRF受体信号机制研究CRF对尼古丁剥夺的影响 以及该信号级联的下游靶点CREB(cAMP反应元件结合蛋白)。 总之，这些研究将对尼古丁缺乏背后的分子机制提供见解。 对这些机制的全面了解将为成功的 尼古丁成瘾的治疗。

Nicotine reward is an integral part of the addictive nature of nicotine, however, smoking and relapse to smoking are often motivated by the desire to alleviate negative affect and deficits in cognitive performance. Moreover, nicotine abstinence symptoms that promote smoking relapse are most evident in the first few days after quitting, suggesting this as a critical period to investigate neural mechanisms that may contribute to smoking relapse. To date, the underlying circuitry and mechanism(s) associated with alterations in emotional processing and learning and memory following nicotine deprivation have not been elucidated. Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. In particular, the mouse is a tractable model that allows for dissection of these mechanisms at a molecular and genetic level not afforded by human studies. Therefore, the overall goal of this project is to characterize novel phenotypes in mice to determine the effects of the early period of nicotine deprivation. Specifically, in Aim 1 we will determine the effects of nicotine deprivation on brain stimulation reward (BSR) and contextual learning and working memory. We hypothesize that chronic nicotine administration alters neural processes underlying affect and learning and memory such that when chronic exposure ceases, anhedonia and deficits in learning and memory will emerge. In order to increase our ability to develop novel therapeutic approaches to treat nicotine dependence, it is important to validate the use of our preclinical models and behavioral phenotypes with clinically effective medications. Therefore, in aim 2 we will evaluate the effects of systemic administration of varenicline (Chantix) on brain stimulation reward (BSR) and contextual learning and working memory following nicotine deprivation. As smokers often report stress relief as a motivating factor contributing to continued smoking behavior, we will investigate a role for stress factors (CRF) during the period of early nicotine deprivation. Thus, in aim 3, we will delineate the molecular mechanisms associated with nicotine deprivation through investigations of CRF by evaluating CRF receptor signaling mechanisms and a downstream target of this signaling cascade, CREB (cAMP response element binding protein). Together these studies will provide insights into the molecular mechanisms underlying nicotine deprivation. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.