Neuropeptide-based therapies for nicotine dependence

描述（由申请人提供）：烟草依赖是一种以强迫性吸烟和戒烟后出现戒断综合征为特征的疾病。尼古丁是烟草烟雾中引起依赖的主要精神活性成分。吸烟与几乎所有器官的癌症和大量慢性疾病有关。据估计，吸烟每年导致44万美国人死亡，并使吸烟者的寿命平均缩短14年。负强化过程（即，快感缺乏）有助于维持吸烟。大多数吸烟者在尝试戒烟后一周内复发，此时情感戒断症状最严重。这表明，逆转尼古丁戒断综合征的治疗可能会显着增加戒烟尝试的成功率。因此，我们研究的总体目标是调查可能介导尼古丁戒断情感症状的神经元底物。将使用大鼠颅内自我刺激范例评估尼古丁戒断的情感体征。大鼠的尼古丁戒断与大脑奖赏阈值的升高有关（即，大脑奖赏功能的缺陷），类似于吸烟者在尝试戒烟时所经历的快感缺失。第一个具体的目的是研究尼古丁戒断过程中杏仁核部分区域的“应激”肽促肾上腺皮质激素释放因子（CRF）的作用。延伸杏仁核是一个涉及情感和动机的大型大脑结构。预期在大鼠中，扩展杏仁核的亚组分中CRF受体的拮抗作用逆转尼古丁戒断的情感体征。第二个具体的目的是研究尼古丁戒断中杏仁核亚组分中的“抗应激”肽神经肽Y（NPY）的作用。预期刺激延伸杏仁核的部分中的NPY受体将减轻情感性尼古丁戒断体征。这些拟议的研究将提供有关尼古丁戒断的神经系统的信息，从而有助于开发新的和改进的戒烟药物疗法。

DESCRIPTION (provided by applicant): Tobacco dependence is a disorder characterized by compulsive tobacco smoking and the appearance of a withdrawal syndrome upon the cessation of tobacco smoking. Nicotine is the major psychoactive ingredient of tobacco smoke that induces dependence. Tobacco smoking has been associated with cancers in nearly all organs and a large number of chronic diseases. It has been estimated that smoking leads to the death of 440,000 Americans each year and reduces the life span of smokers by and average of 14 years. Negative reinforcement processes (i.e., anhedonia) contribute to the maintenance of tobacco smoking. A majority of the tobacco smokers relapse within one week after their cessation attempt when affective withdrawal symptoms are most severe. This suggests that treatments that reverse the nicotine withdrawal syndrome may significantly increase the rates of successful smoking cessation attempts. Therefore, the overall aim of our studies is to investigate the neuronal substrates that may mediate the affective symptoms of nicotine withdrawal. The rat intracranial self-stimulation paradigm will be used to assess the affective signs of nicotine withdrawal. Nicotine withdrawal in rats is associated with elevations in brain reward thresholds (i.e., deficit in brain reward function) that are analogous to the anhedonia experienced by smokers upon a cessation attempt. The first specific aim is to examine the role of the "stress" peptide corticotropin-releasing factor (CRF) in parts of the extended amygdala in nicotine withdrawal. The extended amygdala is a large brain structure involved in emotion and motivation. It is expected that antagonism of CRF receptors in subcomponents of the extended amygdala reverse the affective signs of nicotine withdrawal in rats. The second specific aim is to examine the role of the "anti-stress" peptide neuropeptide Y (NPY) in subcomponents of the extended amygdala in nicotine withdrawal. It is expected that stimulation of NPY receptors in parts of the extended amygdala will alleviate the affective nicotine withdrawal signs. These proposed studies will provide information about the neuronal systems underlying nicotine withdrawal and may thereby contribute to the development of new and improved pharmacotherapies for smoking cessation.