The Role of CREB and Opioid System in Nicotine Reward

尼古丁依赖的动物模型对于研究与这种成瘾相关的分子机制至关重要。小鼠是一种易于处理的模型，可以在人类研究无法提供的水平上解剖这些机制。特别是，基因改变的小鼠可用于分析各种复杂的功能，包括与成瘾相关的功能。各种滥用药物，如吗啡，可卡因和最近的尼古丁，已被证明可以激活大脑中的转录因子CREB（CAMP反应元件结合蛋白）。我们将利用CREB靶向突变纯合小鼠（CREBaD突变小鼠）来检验CREB是尼古丁成瘾特性所需的中心信号分子的假设。我们将在三个具体目标中检验这一核心假设。首先，我们将研究转录因子CREB的激活是否是尼古丁奖赏效应的关键表现，使用条件性位置偏好范式（CPP）对野生型和非野生型尼古丁进行研究。 CREBaD突变小鼠。接下来，我们将确定CREB是否对尼古丁戒断的厌恶效应的表现和/或负责维持尼古丁奖赏的潜在机制至关重要。我们将用尼古丁治疗野生型和CREBaD突变小鼠，并评估戒断的身体（躯体体征）和心理（条件性位置厌恶）体征。此外，戒断期对随后奖励的影响 还将评价尼古丁的性质。最后，我们将确定尼古丁的奖赏特性是否通过内源性阿片系统介导，以及是否以CREB依赖的方式发生。我们将利用阿片受体拮抗剂纳洛酮，以及mv-阿片受体基因敲除小鼠，以评估CREB激活和行为反应的变化，在条件性位置偏爱急性和慢性尼古丁给药。总之，这些研究将为尼古丁奖赏的分子机制以及尼古丁与内源性阿片系统之间的相互作用提供见解。对这些机制的全面了解将为成功治疗尼古丁成瘾开辟新的前景。

Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. The mouse is a tractable model that allows for dissection of these mechanisms at a level not afforded by human studies. In particular, genetically-altered mice can be used to analyze a variety of complex functions including those associated with addiction. A variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, have been shown to activate the transcription factor CREB (CAMP response element binding protein) in the brain. We will utilize mice homozygous for a targeted mutation in CREB (CREBaD mutant mice) to test the hypothesis that CREB is a central signaling molecule required for the addictive properties of nicotine. We will test this central hypothesis in three specific aims. First, we will investigate if activation of the transcription factor CREB is critical for the manifestation of rewarding effects of nicotine using a conditioned place preference paradigm (CPP) for nicotine in wild type and CREBaD mutant mice. Next, we will determine if CREB is critical for the manifestation of aversive effects of nicotine withdrawal and/or the underlying mechanism responsible for the maintenance of nicotine reward. We will treat wild type and CREBaD mutant mice with nicotine and evaluate both physical (somatic signs) and psychological (conditioned place aversion) signs of withdrawal. Furthermore, the effects of a withdrawal period on subsequent rewarding properties of nicotine will also be evaluated. Lastly, we will establish if the rewarding properties of nicotine are mediated through the endogenous opioid system, and if this occurs in a CREB dependent manner. We will utilize the opioid receptor antagonist naloxone, as well as mv-opioid receptor knock-out mice to evaluate changes in CREB activation and behavioral responses in conditioned place preference following acute and chronic nicotine administration. Together, these studies will provide insights into the molecular mechanisms underlying nicotine reward as well as interactions between nicotine and the endogenous opioid system. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.