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

描述(由申请者提供)：青少年中的烟草滥用是一个主要的健康和经济问题，但关于调节青少年吸烟行为的机制存在严重的知识差距。我们的初步数据显示，与成年大鼠相比，青春期雄性大鼠表现出更强的尼古丁奖励和更少的尼古丁戒断。这项建议通过研究尼古丁奖赏和戒断的行为效应中调节发育敏感性和性别差异的神经机制，扩展了我们之前的工作。为了研究青少年尼古丁暴露所产生的长期后果，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伏隔核(NAcc)中增强的多巴胺(DA)传递来调节的。相反，尼古丁戒断会导致NAcc DA水平的下降。NAcc DA传递的改变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的DA投射。在青春期，调节DA的兴奋系统过度发达，而抑制系统不发达。我们假设，与成年人相比，青少年将表现出更强的尼古丁奖赏和更少的尼古丁戒断。这些发育差异可能是通过增强对VTA DA细胞体的兴奋和减少对VTA DA细胞体的抑制来调节的。总体而言，我们预计这些差异在女性青少年和预先接触尼古丁的大鼠中将被放大。这是基于临床研究表明，在青春期预先接触尼古丁的青少年女性和成年人对长期烟草滥用的易感性增加。行为学研究将比较使用地点偏好程序的尼古丁奖励和使用地点厌恶程序的尼古丁戒断。神经化学研究将使用体内微透析程序来比较NAcc DA和伴随的尼古丁给药后和戒烟期间VTA中兴奋和抑制系统的测量。这项研究意义重大，因为我们的发现可能对指导针对青少年和女性的烟草监管和警告的公共政策具有重大影响。此外，更好地了解青少年烟草滥用的调节机制将有助于对最有可能因长期吸烟而患上疾病的年轻吸烟者提供更有效的治疗。

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.