Crosstalk between dopamine and glucocorticoids in high levels of nicotine intake and anhedonia in rats

摘要 吸烟会上瘾，大多数吸烟者都想戒烟。然而，即使接受治疗，也只有很小的一部分 吸烟者成功戒烟的百分比。临床研究表明，戒烟会导致快感缺失， 这增加了复发的风险。尼古丁诱导多巴胺(DA)的释放，这在 建立习惯吸烟，而压力系统的激活被认为是中介 戒断和快感缺失。几乎所有的动物研究都是在不依赖的啮齿动物身上进行的 获得尼古丁的途径有限或很短。因此，人们对调解机制知之甚少。 尼古丁摄入量高的依赖动物的戒断和自我给药。开发新的 戒烟治疗，需要更深入地了解调节戒烟的神经生物学机制 通过自身服用尼古丁而成瘾的动物的戒断和尼古丁摄入量。这个 这项研究计划的长期目标是确定薪酬体系中导致高薪酬的适应性 依赖动物的尼古丁摄入量和快感缺乏症水平。我们研究的目标是确定 多巴胺和应激激素皮质酮在依赖动物尼古丁自我给药中的作用 以及戒断性快感缺乏症。提出了使用间歇性长通道模型来获得较高的 尼古丁摄取水平和诱发依赖。我们的初步研究表明，DA在高水平的 依赖动物的尼古丁摄入量，以及与戒断相关的快感缺乏症的大脑应激系统。 根据我们的研究，推测多巴胺的传递和糖皮质激素受体(GR)信号在大脑皮层 伏核(NACC)是尼古丁摄取高水平和尼古丁相关快感减退的关键。 戒烟。为了检验这一假设，本文提出了三个目标。1)确定尼古丁与 依赖(长通道)和非依赖(短通道)动物的摄取和奖励功能。2) 确定DA信号在依赖和非依赖动物尼古丁摄取中的作用。3)确定 DA-CORT相互作用在NACC中的作用在尼古丁摄入量和快感缺乏症中的作用 不依赖的动物。为了研究尼古丁摄入量与奖赏功能的关系，男性和 雌性大鼠将准备好静脉导管和颅内自我刺激(ICSS)电极。这个 ICSS方法提供了一种客观衡量奖励函数的方法。多巴胺拮抗剂与转基因D1-Cre D2-CRE大鼠将被用来确定在高水平尼古丁的情况下，D1和D2神经元在NACC中的作用 吸食和撤药。据预测，D1受体在依赖和依赖的尼古丁摄取中起关键作用 不依赖的动物。预计阻断GR也会减少依赖者的尼古丁摄入量。 防止戒断过程中NACC中DA水平的下降，并减少快感缺乏 与尼古丁戒断有关。这些研究将深入了解DA和CORT在NACC中的作用 在依赖动物的高水平尼古丁自我给药和戒断诱导的快感丧失中。

SUMMARY Smoking is addictive and most smokers would like to quit. However, even with treatment, only a small percentage of smokers quits successfully. Clinical studies indicate that smoking cessation leads to anhedonia, which increases the risk for relapse. Nicotine induces the release of dopamine (DA), which plays a role in establishing habitual smoking, while the activation of stress systems has been suggested to mediate withdrawal and anhedonia. Virtually all animal studies have been conducted with nondependent rodents that had limited or short access to nicotine. Therefore, very little is known about the mechanisms that mediate withdrawal and self-administration in dependent animals with high levels of nicotine intake. To develop new smoking cessation treatments, more insight is needed into the neurobiological mechanisms that mediate withdrawal and nicotine intake in animals that have become dependent by self-administering nicotine. The long-term goal of this research program is to determine the adaptations in the reward system that cause high levels of nicotine intake and anhedonia in dependent animals. The objective of our studies is to determine the role of DA and the stress hormone corticosterone (CORT) in nicotine self-administration in dependent animals and withdrawal-induced anhedonia. It is proposed to use an intermittent long access model to obtain high levels of nicotine intake and induce dependence. Our preliminary studies point to a role for DA in high levels of nicotine intake in dependent animals, and brain stress systems in the anhedonia associated with withdrawal. Based on our studies, it is hypothesized that DA transmission and glucocorticoid receptor (GR) signaling in the nucleus accumbens (Nacc) are pivotal for high levels of nicotine intake and anhedonia associated with nicotine withdrawal. Three aims are proposed to test this hypothesis. 1) Determine the relationship between nicotine intake and reward function in dependent (long access) and nondependent (short access) animals. 2) Determine the role of DA signaling in nicotine intake in dependent and nondependent animals. 3) Determine the role of DA-CORT interactions in the Nacc in nicotine intake and anhedonia in dependent and nondependent animals. To investigate the relationship between nicotine intake and reward function, male and female rats will be prepared with intravenous catheters and intracranial self-stimulation (ICSS) electrodes. The ICSS method provides an objective measure of reward function. Dopamine antagonists and transgenic D1-Cre and D2-Cre rats will be used to determine the role of D1 and D2 neurons in the Nacc in high levels of nicotine intake and withdrawal. It is predicted that D1 receptors play a critical role in nicotine intake in dependent and nondependent animals. It is also expected that blockade of GR will decrease nicotine intake in dependent animals, prevents the decrease in DA levels in the Nacc during withdrawal, and diminishes anhedonia associated with nicotine withdrawal. The studies will provide insight into the role of DA and CORT in the Nacc in high levels of nicotine self-administration in dependent animals and withdrawal-induced anhedonia.