Compensation of Nicotine Self-Administration

描述（由申请人提供）：阐明尼古丁可得性降低导致的补偿机制或吸烟行为变化，对于将减少吸烟作为一种管理不愿或无法戒烟的吸烟者烟草依赖的方法至关重要。我们的实验室开发了两种减少吸烟的啮齿动物模型，在这种模型中，在减少每日尼古丁接触时间或每次输注尼古丁剂量后，观察到尼古丁自我给药的代偿性增加。目前的提案将研究尼古丁戒断的负面情感（即情绪）后果的严重程度，如颅内自我刺激阈值升高所评估的，是否预测了剂量或获取减少模型中的补偿。进一步的研究将检验尼古丁特异性单克隆抗体的被动免疫是否能有效减少尼古丁在大脑中的分布并延长药物的半衰期。描述预测因素和补偿治疗方法可能有助于减少吸烟用于治疗尼古丁成瘾，也可能有助于更好地理解调节吸烟行为的机制。与公共卫生的相关性：吸烟是现代世界可预防的死亡和疾病的主要原因。虽然减少吸烟可能会减少香烟的有害影响，但这种策略的有效性可能会受到吸烟行为的代偿性变化（例如，增加每次吸烟的深度）的限制。拟议的研究将试图描述诱发因素和使用两种减少吸烟的动物模型进行补偿的可能治疗，将提供如何限制这种行为的见解，并更好地理解减少吸烟作为一种管理烟草依赖的方法的潜在作用。

DESCRIPTION (provided by applicant): Elucidating the mechanisms underlying compensation, or changes in smoking behavior that occur in response to decreased nicotine availability, is crucial for characterizing smoking reduction as an approach to managing tobacco dependence in smokers who are unwilling or unable to quit. Our laboratory has developed two rodent models of smoking reduction in which compensatory increases in nicotine selfadministration are observed following reductions in duration of daily nicotine access or nicotine dose per infusion. The current proposal will examine whether severity of the negative affective (i.e., emotional) consequences of nicotine withdrawal, as assessed by elevated intracranial self-stimulation thresholds, is predictive of compensation in either the dose or access models of reduction. Additional studies will examine whether passive immunization with a nicotine-specific monoclonal antibody, which decreases nicotine distribution to the brain and prolongs the drug's half-life, is effective in reducing compensation. Characterizing predictors and treatments for compensation may facilitate the use of smoking reduction for the treatment of nicotine addiction, and may also lead to a better understanding of the mechanisms regulating smoking behavior. Relevance to public health: Cigarette smoking is the leading preventable cause of death and disease in the modern world. Although reducing smoking may decrease the harmful effects of cigarettes, the effectiveness of this strategy may be limited by compensatory changes in smoking behavior (for example, increasing the depth of each puff) that occur following smoking reduction. The proposed studies, which will attempt to characterize predisposing factors and a possible treatment for compensation using two animal models of smoking reduction, will provide insights into how to limit this behavior and better understand the potential role of smoking reduction as an approach towards managing tobacco dependence.