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

大鼠高水平尼古丁摄入和快感缺乏中多巴胺和糖皮质激素之间的串扰

• 批准号: 10317039
• 负责人: Adriaan Willem Bruijnzeel
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317039
• 关键词: Acute; Affect; Anhedonia; Animal Model; Animals; Behavior; Brain; Catheters; Clinical Research; Corticosterone; Dependence; Development; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrodes; Enterobacteria phage P1 Cre recombinase; Evaluation; Female; Glucocorticoid Receptor; Glucocorticoids; Goals; Homeostasis; Hormones; Injections; Intake; Intravenous; Knowledge; Lead; Measures; Mediating; Methods; Microdialysis; Modeling; Neurons; Neuropeptides; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Persons; Play; Procedures; Property; Pump; Rattus; Receptor Activation; Receptor Signaling; Relapse; Research; Rewards; Rodent; Role; Self Administration; Self Stimulation; Signal Transduction; Smoke; Smoker; Smoking; Smoking Cessation Intervention; Stress; System; Testing; Time; Tobacco; Transgenic Organisms; Withdrawal; Work; antagonist; base; depressive symptoms; designer receptors exclusively activated by designer drugs; drug relapse; experimental study; insight; male; median forebrain bundle; neurobiological mechanism; nicotine cessation; prevent; programs; relapse risk; smoking addiction; smoking cessation; transmission process; virtual

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.

概括 吸烟会让人上瘾，大多数吸烟者都想戒烟。然而，即使进行了治疗，也只能起到很小的作用。 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乏， 这增加了复发的风险。尼古丁诱导多巴胺（DA）的释放，其在 建立吸烟习惯，同时建议激活压力系统来调节 戒断和快感缺乏。几乎所有的动物研究都是针对非依赖性啮齿类动物进行的， 接触尼古丁的机会有限或短暂。因此，人们对介导的机制知之甚少。 尼古丁摄入量较高的依赖动物的戒断和自我给药。开发新的 戒烟治疗，需要更多地了解介导的神经生物学机制 通过自我施用尼古丁而变得依赖的动物的戒断和尼古丁摄入。这 该研究计划的长期目标是确定奖励系统中导致高 依赖动物的尼古丁摄入量和快感缺乏水平。我们研究的目的是确定 DA 和应激激素皮质酮 (CORT) 在依赖性动物尼古丁自我给药中的作用 和戒断引起的快感缺乏。建议使用间歇长访问模型来获得高 尼古丁摄入量并诱发依赖性。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失中的大脑应激系统。 根据我们的研究，假设 DA 传输和糖皮质激素受体 (GR) 信号在 伏隔核 (Nacc) 对于高水平尼古丁摄入和与尼古丁相关的快感缺失至关重要 撤回。提出了三个目标来检验这一假设。 1）确定尼古丁之间的关系 依赖（长期访问）和非依赖（短期访问）动物的摄入和奖励函数。 2） 确定 DA 信号在依赖和非依赖动物尼古丁摄入中的作用。 3）确定 DA-CORT 相互作用在 Nacc 中对尼古丁摄入和快感缺乏的作用 非依赖性动物。研究尼古丁摄入量与奖赏功能之间的关系，男性和女性 雌性大鼠将准备静脉导管和颅内自刺激（ICSS）电极。这 ICSS 方法提供了奖励函数的客观衡量方法。多巴胺拮抗剂和转基因 D1-Cre D2-Cre 大鼠将用于确定 Nacc 中 D1 和 D2 神经元在高水平尼古丁中的作用 摄入和退出。据预测，D1 受体在依赖和依赖尼古丁的人群中发挥着关键作用。 非依赖性动物。还预计 GR 的封锁将减少依赖者的尼古丁摄入量 动物，防止戒断期间 Nacc 中 DA 水平的下降，并减少快感缺失 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 依赖动物的高水平尼古丁自我给药和戒断引起的快感缺乏。