Adolescence: A Sensitive Period for Nicotine Addiction

青春期：尼古丁成瘾的敏感期

• 批准号: 7213403
• 负责人: EDWARD D LEVIN
• 金额: $ 21.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213403
• 关键词: Accounting; Address; Adolescence; Adolescent; Adult; Age; Animal Model; Blood; Body Burden; Body Weight; Brain; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical; Cocaine; Cocaine Dependence; Condition; Data; Dependence; Development; Dose; Drug Kinetics; Female; Gender; Genetic; Goals; Human; Infusion procedures; Intake; Life; Literature; Measurement; Metabolism; Modeling; Nature; Nicotine; Nicotine Dependence; Nicotinic Agonists; Nicotinic Antagonists; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Predisposition; Randomized; Range; Rate; Rattus; Research; Role; Running; Selection Bias; Self Administration; Self-Administered; Sex Characteristics; Smoker; Smoking; Speed; Suggestion; System; Testing; Therapeutic; Tobacco Dependence; Tobacco use; Training; Treatment Protocols; United States Public Health Service; Week; Withdrawal; addiction; adolescent smoking; age effect; age related; base; drug development; improved; male; neurobehavioral; neurodevelopment; nicotine patch; nicotine replacement; osmotic minipump; research study; response; smoking cessation

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.

描述（由申请人提供）：绝大多数烟草成瘾始于青少年时期，但与成人相比，对尼古丁对青少年神经行为的影响知之甚少。青少年在走向成年的道路上仍在经历重要的神经发育变化。青少年时期的尼古丁暴露可能对这种晚期神经发育产生持久影响。临床文献中有建议称，成瘾程度较高的吸烟者在青春期更早开始吸烟，但青春期尼古丁自我给药与自我选择偏见（即更容易重度成瘾的人也更早开始吸烟）的影响，在伦理上不可能在人类中没有混淆。这个项目是基于我们的假设，在青春期开始尼古丁自我管理导致更大的尼古丁摄入量和依赖性比在成年期开始。我们的初步数据表明，在尼古丁自我给药大鼠模型中，尼古丁自我给药起效的大鼠自我给药的尼古丁总剂量显著高于成年发作大鼠，这种较高的尼古丁自我给药率持续到成年期，尼古丁自我给药率约为成年期的两倍。 拟定的实验将确定起效尼古丁自我给药与增强的长期尼古丁自我给药之间的因果关系，这些特定目的。 1.测定尼古丁在青少年和成年大鼠体内的药代动力学和量效函数。 2.确定尼古丁替代和尼古丁拮抗剂治疗对尼古丁自我给药的影响。 3.确定成人尼古丁自我给药的年龄阈值。 4.确定青少年开始自行服用尼古丁是否会增强可卡因依赖性。 5.确定发作性尼古丁自我给药的性别差异。将使用青少年和成年大鼠中的尼古丁药代动力学测量值来确定分布和代谢改变与药效学因素对尼古丁自我给药年龄相关差异的影响。 这项研究的好处包括一个更相关的动物模型的初发性吸烟，更好地了解初发性尼古丁的使用如何增强尼古丁的摄入量，原因和影响的青少年尼古丁使用的网关假设的确定导致更难的药物和开发更好的治疗初发性尼古丁依赖。