Compensation of Nicotine Self-Administration

说明(申请人提供)：阐明补偿机制，或尼古丁可获得性下降引起的吸烟行为变化，对于将减少吸烟描述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。我们实验室已经建立了两种减少吸烟的啮齿动物模型，在这两种模型中，尼古丁自身给药的代偿性增加是随着每日尼古丁获取时间或每次尼古丁注射剂量的减少而观察到的。目前的建议将审查尼古丁戒断的负面情感(即情感)后果的严重性，如通过升高的颅内自我刺激阈值来评估，是否预示着减少的剂量或获得模式中的补偿。其他研究将检验尼古丁特异性单抗被动免疫是否在减少补偿方面有效，这种抗体减少尼古丁在大脑中的分布，并延长药物的半衰期。确定补偿的预测因素和治疗方法可能有助于使用戒烟治疗尼古丁成瘾，也可能有助于更好地理解吸烟行为的调节机制。与公众健康相关：吸烟是现代世界主要的可预防的死亡和疾病原因。虽然减少吸烟可能会减少香烟的有害影响，但这一策略的有效性可能会受到减少吸烟后吸烟行为的补偿性变化(例如，增加每次吸烟的深度)的限制。这项拟议的研究将试图利用两种吸烟减少的动物模型来表征诱因和可能的补偿治疗，将为如何限制这种行为提供见解，并更好地理解减少吸烟作为控制烟草依赖的一种方法的潜在作用。

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.