Adolescence: A Sensitive Period for Nicotine Addiction

说明(申请人提供)：绝大多数烟草成瘾始于青春期，但与成年人相比，人们对尼古丁对青少年神经行为的影响知之甚少。青少年在成年过程中仍在经历重要的神经发育变化。青春期接触尼古丁可能会对这种晚期神经发育产生持久的影响。临床文献表明，烟瘾越严重的吸烟者在青春期就开始吸烟的时间越早，但在人类身上，尼古丁自我管理与自我选择偏见的影响--更容易上瘾的人也更早开始吸烟--在伦理上是不可能没有混淆的。这个项目是基于我们的假设，在青春期开始自我服用尼古丁会导致更多的尼古丁摄入和依赖，而不是从成年开始。我们的初步数据表明，在尼古丁自我给药的大鼠模型中，青春期起病的尼古丁自我给药的大鼠比成年起病的大鼠摄入的尼古丁总剂量要高得多，这种更高的尼古丁自我给药比率持续到成年，尼古丁自我给药的比例大约翻了一番。 拟议的实验将确定青春期开始的尼古丁自我给药和增强的长期尼古丁自我给药之间的因果关系，并实现这些特定目标。 1.测定尼古丁在青春期和成年大鼠体内的药代动力学和量效关系。 2.确定尼古丁替代疗法和尼古丁拮抗剂治疗对青少年和成人尼古丁自我给药的影响。 3.确定成人型尼古丁自我给药的年龄阈值。 4.确定青春期开始的尼古丁自我管理是否会增加可卡因依赖。 5.确定青少年尼古丁自我给药的性别差异。尼古丁在青春期和成年大鼠体内的药代动力学测量将被用来确定改变分布和代谢与药效学因素在解释与年龄相关的尼古丁自我给药差异方面的效果。 这项研究的好处包括一个更相关的青少年开始吸烟的动物模型，更好地理解青少年开始使用尼古丁如何增加尼古丁的摄入量，确定青少年使用尼古丁导致更难的药物的门户假设的因果关系，以及开发更好的治疗青少年开始的尼古丁依赖的方法。

DESCRIPTION (provided by applicant): The great majority of tobacco addiction begins during adolescence, but very little is known about the neurobehavioral effects of nicotine in adolescents compared to adults. Adolescents are still undergoing important neurodevelopmental changes on the path to adulthood. Nicotine exposure in adolescence may have lasting impacts on this late neurodevelopment. There are suggestions in the clinical literature that more heavily addicted smokers begin smoking earlier in adolescence, but the impact of nicotine self-administration during adolescence versus self-selection bias whereby people more prone to heavy addiction also begin earlier, cannot be ethically unconfounded in humans. This project is based on our hypothesis beginning nicotine self-administration during adolescence leads to greater nicotine intake and dependence than beginning in adulthood. Our preliminary data demonstrated in the rat model of nicotine self-administration that rats with adolescent-onset nicotine self-administration self-administer substantially higher total doses of nicotine than adult-onset rats, This higher rate of nicotine self-administration continues into adulthood with an approximate doubling of nicotine self-administration. The proposed experiments will determine the causal relationship between adolescent-onset nicotine self-administration and enhanced long-term nicotine self-administration with these Specific Aims. 1. Determine the pharmacokinetics and dose-effect functions of nicotine in adolescents and adult rats. 2. Determine the impact of nicotine replacement and nicotinic antagonist therapy on nicotine self-administration in adolescent-onset and adult-onset nicotine self-administration. 3. Determine the age threshold for the adult-like nicotine self-administration. 4. Determine if adolescent-onset nicotine self-administration enhances cocaine dependence. 5. Determine sex differences in adolescent-onset nicotine self-administration. Nicotine pharmacokinetic measurements in adolescent and adult rats will be used to determine the effect of altered distribution and metabolism versus pharmacodynamic factors in accounting for age-related differences in nicotine self-administration. Benefits of this research include a more relevant animal model of adolescent-onset smoking, improved understanding of how adolescent-onset nicotine use potentiates nicotine intake, a cause and effect determination of the gateway hypothesis of adolescent nicotine use leading to harder drugs and the development of better treatments for adolescent-onset nicotine dependence.