Project 2: Nicotine exposure reduction in rats

这项建议的目标是开发减少尼古丁暴露的动物模型，并利用这些模型来研究补偿的决定因素、补偿的后果以及促进减少的潜在干预措施。对于不能或不愿戒烟的吸烟者来说，减少吸烟是戒烟的替代选择，或者是向戒烟过渡的目标。然而，由于吸烟行为的补偿性变化，有意义地减少吸烟很难实现。了解补偿机制对于评估减少吸烟作为一种治疗策略的可行性、选择这一方法的候选者以及开发促进减少吸烟的干预措施非常重要。在这个项目中，将使用接受尼古丁自我给药(NSA)训练的大鼠来检验两种减少尼古丁暴露的模型；尼古丁自我给药的持续时间从23h/d减少到2小时/d，NSA剂量从0.06 mg/kg/次减少到0.03 mg/kg/次。具体目标1是确定薪酬的潜在决定因素。研究将把代偿程度与基线尼古丁摄入量、每日尼古丁摄取模式、尼古丁清除和消除半衰期以及终止尼古丁注射后的报酬赤字联系起来，以颅内自我刺激阈值衡量。具体目标2是评估尼古丁暴露减少对随后的重新获得的影响。这些实验将研究尼古丁的潜在不良后果。 减少暴露；当尼古丁的获取不再受到限制时，是否保持与补偿相关的增加的应答率，从而导致国家安全局的比率高于基线。具体目标#3是研究接种尼古丁疫苗对NSA补偿的影响。由于接种尼古丁疫苗显著延长了尼古丁的消除半衰期，我们将研究它是否会减少补偿，从而促进尼古丁暴露的减少。具体目标4是研究怀孕对NSA和补偿的影响。许多妇女在怀孕期间减少吸烟，孕妇减少吸烟已被证明可以改善生育结果，从而确定了这一干预措施的关键目标人群。我们将研究NSA是否会因怀孕而改变，以及怀孕对补偿的影响。这些数据应该有助于理解补偿的决定因素，确定减少补偿的潜在策略，以及确定可能可行的个人或人群。该项目提供了我们中心对减少烟草暴露在全面烟草控制战略中的作用的垂直综合调查的临床前组成部分。在……里面 此外，这项研究与Hatsukami博士关于减少吸烟的人体实验室研究平行，并提供了补充信息。

The goal of this proposal is to develop animal models of nicotine exposure reduction and to use these to study the determinants of compensation, the consequences of compensation, and potential interventions to facilitate reduction. Smoking reduction is of interest as an alternative to cessation, or as a transitional goal toward cessation, for smokers who cannot or will not quit. However, meaningful reduction of smoke intake is difficult to achieve because of compensatory changes in smoking behavior. Understanding the mechanisms underlying compensation is important for assessing the viability of smoking reduction as a treatment strategy, selection of candidates for this approach, and development of interventions to facilitate reduction. In this project, 2 models of nicotine exposure reduction will be examined using rats trained for nicotine self-administration (NSA); reduction of access duration from 23 h/d to 2 h/d, and reduction of the NSA dose from 0.06 to 0.03 mg/kg/infusion. Specific Aim #1 is to identify potential determinants of compensation. Studies will relate the degree of compensation to baseline nicotine intake, diurnal nicotine intake pattern, nicotine clearance and elimination half-life, and reward deficit after termination of a nicotine infusion as measured by intracranial self-stimulation thresholds. Specific Aim #2 is to assess the effects of nicotine exposure reduction on subsequent reacquisition. These experiments will study a potential adverse consequence of nicotine exposure reduction; whether the increased response rate associated with compensation is maintained when access to nicotine is no longer restricted, resulting in higher than baseline NSA rates. Specific Aim # 3 is to study the effects of vaccination against nicotine on NSA compensation. Because vaccination against nicotine markedly prolongs nicotine's elimination half-life, we will study whether it reduces compensation and thereby facilitates nicotine exposure reduction. Specific Aim #4 is to study the effects of pregnancy on NSA and compensation. Many women reduce their smoking during pregnancy, and smoking reduction in pregnant women has been shown to improve birth outcomes, thus identifying a key target population for this intervention. We will study whether NSA is altered by pregnancy, and the effects of pregnancy on compensation. These data should be helpful in understanding the determinants of compensation, identifying potential strategies to reduce compensation, and identifying individuals or populations in whom smoking reduction is likely to be feasible. This project provides the preclinical component of our Center's vertically integrated investigation of the role of tobacco exposure reduction in a comprehensive tobacco control strategy. In addition, this study parallels and provides complementary information to Dr. Hatsukami's human laboratory studies of smoking reduction.