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

总结 吸烟会上瘾，大多数吸烟者都想戒烟。然而，即使经过治疗， 吸烟者成功戒烟的比例。临床研究表明，戒烟会导致快感缺失， 这会增加复发的风险尼古丁诱导多巴胺（DA）的释放，多巴胺在 建立习惯性吸烟，而压力系统的激活被认为是介导 戒断和快感缺乏。几乎所有的动物研究都是用非依赖性啮齿动物进行的， 尼古丁摄入量有限或很短。因此，对介导的机制知之甚少。 在尼古丁摄入水平较高的依赖性动物中进行戒断和自我给药。开发新 戒烟治疗，需要更多的了解神经生物学机制，介导 戒断和尼古丁摄入的动物已经成为依赖自我管理尼古丁。的 这项研究计划的长期目标是确定奖励系统中的适应性， 尼古丁摄入水平和依赖动物的快感缺乏。我们研究的目的是确定 DA和应激激素皮质酮（CORT）在依赖动物尼古丁自我给药中的作用 和戒断引起的快感缺失建议使用间歇性长访问模型来获得高 尼古丁的摄入量和诱导依赖性。我们的初步研究指出，DA在高水平的 依赖性动物的尼古丁摄入，以及与戒断相关的快感缺乏中的大脑应激系统。 基于我们的研究，我们假设多巴胺传递和糖皮质激素受体（GR）信号在脑内的表达与多巴胺受体（GR）的表达有关。 延髓核（Nacc）是高水平尼古丁摄入和与尼古丁相关的快感缺乏的关键 戒断提出了三个目标来检验这一假设。1)确定尼古丁与 依赖性（长时间接触）和非依赖性（短时间接触）动物的摄入和奖励功能。（二） 确定依赖和非依赖动物中DA信号在尼古丁摄入中的作用。3)确定 DA-CORT在Nacc中的相互作用在尼古丁摄入和快感缺乏中的作用 不依赖的动物为探讨尼古丁摄入量与奖赏功能的关系， 将用静脉内导管和颅内自刺激（ICSS）电极准备雌性大鼠。的 ICSS方法提供了一种客观的报酬函数度量方法。多巴胺拮抗剂和转基因D1-Cre 和D2-Cre大鼠将用于确定在高水平尼古丁下Nacc中D1和D2神经元的作用 摄入和退出。据预测，D1受体在依赖性和非依赖性尼古丁摄入中起关键作用， 不依赖的动物还预期GR的阻断将减少依赖性吸烟者的尼古丁摄入。 动物，防止在戒断期间Nacc中DA水平的降低，并减少快感缺乏 与尼古丁戒断有关。这些研究将为深入了解DA和CORT在Nacc中的作用提供帮助。 在依赖性动物中高水平的尼古丁自我给药和戒断诱导的快感缺乏中。

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.