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

青少年中的烟草滥用是一个主要的健康和经济问题，但有一个关键的 关于调节青少年吸烟行为的机制的知识差距。我们的初步数据 证明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 相对于成年人来说。这项建议通过检查神经机制来扩展我们之前的工作 尼古丁奖赏的行为效应在发育敏感性和性别差异中起中介作用 戒烟。为了研究青少年接触尼古丁所产生的长期后果，我们的 该提案还包括在青春期预先暴露于尼古丁的成年大鼠。尼古丁奖赏是由 部分是通过增强伏核(NAcc)中的多巴胺(DA)传递。相比之下，尼古丁 停药会导致NAcc DA水平下降。NAcc DA传递的变化是由 调节起源于腹侧被盖区的DA投射的兴奋和抑制系统 (VTA)。在青春期，调节DA的兴奋系统过度发育，而抑制 系统还不发达。我们假设青少年会表现出更强的尼古丁奖赏 与成年人相比，尼古丁的戒断减少了。这些发育差异很可能是通过 增强VTA DA胞体的兴奋和减少抑制作用。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会放大。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接触尼古丁的表现 增加了长期烟草滥用的脆弱性。行为研究将比较尼古丁奖赏与 地点偏爱程序和尼古丁戒断使用地点厌恶程序。神经化学 研究将采用体内微透析程序来比较NAcc DA和伴随的措施 尼古丁给药后和戒烟期间VTA中的兴奋和抑制系统。 这项研究意义重大，因为我们的发现可能对引导公众具有重大意义 针对青少年和女性的烟草管制和警告政策。更进一步，更好的 了解青少年烟草滥用的调节机制将有助于更有效的治疗 适用于长期吸烟而罹患疾病风险最高的年轻吸烟者。

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 nicotinewithdrawal 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.