CORTICOSTEROIDS, STRESS, AND NICOTINE DEPENDENCE

最近的动物研究表明，皮质类固醇下调了 尼古丁受体，导致对尼古丁的敏感性降低 可能有助于解释急性和慢性耐受现象。 尼古丁。这一观察结果对理解尼古丁的意义 人类通过吸烟获得的自我管理是尼古丁摄入量增加 在心理压力或其他情况下 皮质类固醇水平升高可能代表行为补偿 针对特定情况下尼古丁敏感性的降低。长期的 拟议项目的目标是探索皮质类固醇的作用 尼古丁敏感性的调节和尼古丁自身的调节机制 吸烟者的管理。在5年的时间里，研究分为三个阶段 将使用重复测量设计对男性受试者21至 45岁。第一阶段的具体目标是确定影响 通过吸烟影响尼古丁自身给药的皮质类固醇活性 使用不同剂量的合成皮质类固醇，地塞米松 (IA)；测试以下情况增加尼古丁摄入量的可能性 地塞米松是吸烟行为非特异性增强的结果 通过比较尼古丁香烟和非尼古丁香烟的吸烟量；以及 不同皮质类固醇受体激动剂的作用特征 (氟可的松、氢化可的松和地塞米松)对 尼古丁，由心率和皮质醇增加和核心 静脉注射固定药物后体温下降 尼古丁剂量(IC)。第二阶段的目标是研究 已知增加的不同水平的心理应激源的影响 吸烟对尼古丁摄入量的皮质类固醇活性(心算) (IIa)和静脉注射尼古丁后对尼古丁的敏感性 固定尼古丁剂量(IIC)；并测试增加 尼古丁摄入是应激诱导的增强的副作用 比较吸烟中尼古丁和非尼古丁的吸烟行为 香烟(IIB)。第三阶段的目标是研究相互作用 尼古丁依赖--反映了慢性耐受性的差异-- 以及在第一阶段和第二阶段通过改变剂量来研究的变量 地塞米松对高度依赖和较少依赖的吸烟者(IIIA)； 通过呈现这些吸烟者对压力的反应来表征 不同程度的心理压力源(IIIB)；以及确定 尼古丁敏感性是否与高血压病史不可逆转地联系在一起 通过检测尼古丁输注对高度肥胖患者的影响来研究尼古丁的使用 依赖吸烟者、不依赖吸烟者、前吸烟者和从不吸烟者 地塞米松或安慰剂(IIIC)。总体而言， 该项目旨在确定其澄清可能会增加 了解吸烟和尼古丁依赖并导致 开发治疗吸烟的新工具。

Recent animal research suggests that corticosteroid down-regulation of the nicotine receptor, resulting in decreased sensitivity to nicotine's effects, may help to explain the phenomena of acute and chronic tolerance to nicotine. An implication of this observation for understanding nicotine self-administration via smoking in humans is that increased nicotine intake in the context of psychological stress or other conditions where corticosteroid levels are enhanced may represent behavioral compensation for situation-specific decreases in nicotine sensitivity. The long-term objective of the proposed project is to explore the role of corticosteroid mechanisms in modulating nicotine sensitivity and modifying nicotine self- administration in smokers. Over a 5-year period, three Phases of research will be conducted using repeated-measures designs with male subjects 21 to 45 years of age. The specific aims of Phase I are to determine the effects of corticosteroid activity upon nicotine self-administration via smoking by administering different doses of a synthetic corticosteroid, dexamethasone (IA); to test the possibility that increased nicotine intake following dexamethasone is the result of non-specific enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IB); and to characterize the effects of different corticosteroid receptor agonists (fludrocortisone, hydrocortisone, and dexamethasone) upon sensitivity to nicotine, as defined by heart rate and cortisol increases and core temperature decreases in response to intravenous administration of a fixed dose of nicotine (IC). The objectives of Phase II are to examine the effects of different levels of a psychological stressor known to increase corticosteroid activity (mental arithmetic) on nicotine intake via smoking (IIA) and on sensitivity to nicotine following intravenous administration of a fixed nicotine dose(IIC); and to test the possibility that increased nicotine intake occurs as a side effect of stress-induced enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IIB). The goal of Phase III is to study the interactions between nicotine dependence--reflecting differences in chronic tolerance-- and the variables studied in Phases I & II by varying the dosage od dexamethasone in both highly-dependent and less-dependent smokers (IIIA); to characterize the response to stress in such smokers by presenting different levels of a psychological stressor (IIIB); and to determine whether sensitivity to nicotine is associated irreversibly with history of nicotine use by examining the effects of nicotine infusion in highly- dependent smokers, less-dependent smokers, ex-smokers, and never-smokers following dexamethasone or placebo administration (IIIC). Overall, the project seeks to identify mechanisms whose elucidation may increase the understanding of smoking and nicotine dependence and lead to the development of new tools for treating smoking.