Nico-teen: Mechanisms of Nicotine Reward and Withdrawal During Adolescence

描述（由申请人提供）：青少年中的烟草滥用是一个主要的健康和经济问题，但在介导青少年吸烟行为的机制方面存在关键的知识差距。我们的初步数据表明，青春期雄性大鼠显示增强尼古丁奖励和减少尼古丁戒断相对于成年人。这个建议扩展了我们以前的工作，通过检查神经机制，介导的发展敏感性和性别差异的行为。尼古丁奖励和戒断的影响。为了研究青少年尼古丁暴露产生的长期后果，我们的建议还包括在青春期预先暴露于尼古丁的成年大鼠。尼古丁奖赏部分是通过增强的多巴胺（DA）在延髓核（NAcc）中的传递来介导的。相反，尼古丁戒断会导致NAcc DA水平下降。NAcc DA传递的变化是由兴奋和抑制系统介导的，这些系统调节起源于腹侧被盖区（VTA）的DA投射。在青春期，调节DA的兴奋性系统过度发育，而抑制性系统则不发达。我们假设，相对于成年人，青少年将表现出增强的尼古丁奖励和减少的尼古丁戒断。这些发育差异可能是通过增强兴奋和减少抑制腹侧被盖区DA细胞体介导的。总体而言，我们预计这些差异将在雌性青少年和尼古丁预暴露大鼠中放大。这是基于临床研究，表明青少年女性和成年人在青春期预先暴露于尼古丁显示出对长期烟草滥用的脆弱性。行为研究将比较使用位置偏好程序的尼古丁奖励和使用位置厌恶程序的尼古丁戒断。神经化学研究将采用体内微透析程序比较尼古丁给药后和尼古丁戒断期间VTA中的NAcc DA和兴奋性和抑制性系统的伴随测量。这项研究意义重大，因为我们的研究结果可能对指导针对青少年和女性的烟草管制和警告的公共政策产生重大影响。此外，更好地了解青少年烟草滥用的介导机制将导致对年轻吸烟者的更有效治疗，他们最有可能患上由长期吸烟引起的疾病。

DESCRIPTION (provided by applicant): Tobacco abuse among adolescents is a major health and economic concern, yet there is a critical knowledge gap regarding the mechanisms that mediate adolescent smoking behavior. Our preliminary data demonstrate that adolescent male rats display enhanced nicotine reward and reduced nicotine withdrawal relative to adults. This proposal extends our previous work by examining the neural mechanisms that mediate developmental sensitivity and sex differences in the behavioral .effects of nicotine reward and withdrawal. In order to study the long-term consequences produced by adolescent nicotine exposure, our proposal also includes adult rats pre-exposed to nicotine during adolescence. Nicotine reward is mediated in part by enhanced dopamine (DA) transmission in the nucleus accumbens (NAcc). In contrast, nicotine withdrawal produces a decrease in NAcc DA levels. Changes in NAcc DA transmission are mediated by excitatory and inhibitory systems that regulate DA projections that originate in the ventral tegmental area (VTA). During adolescence, excitatory systems that regulate DA are overdeveloped, whereas inhibitory systems are underdeveloped. We hypothesize that adolescents will display enhanced nicotine reward and reduced nicotine withdrawal relative to adults. These developmental differences are likely mediated via enhanced excitation and reduced inhibition of VTA DA cell bodies. Overall we expect that these differences will be magnified in female adolescents and nicotine pre-exposed rats. This is based on clinical studies demonstrating that teenage females and adults pre-exposed to nicotine during adolescence display enhanced vulnerability to long-term tobacco abuse. Behavioral studies will compare nicotine reward using place preference procedures and nicotine withdrawal using place aversion procedures. Neurochemical studies will employ in vivo microdialysis procedures to compare NAcc DA and concomitant measures of excitatory and inhibitory systems in the VTA following nicotine administration and during nicotine withdrawal. This research is significant because our findings may have significant implications towards guiding public policies regarding tobacco regulation and warnings directed at teenagers and females. Further, a better understanding of the mechanisms mediating adolescent tobacco abuse will lead to more effective treatments for young smokers who are most at risk of developing diseases caused by long-term smoking.