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

Nico-teen：青春期尼古丁奖赏和戒断机制

• 批准号: 7587355
• 负责人: LAURA ELENA ODELL
• 金额: $ 35.07万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587355
• 关键词: Adolescence; Adolescent; Adult; Age; Behavioral; Clinical Research; Data; Development; Disease; Dopamine; Equilibrium; Female; Female Adolescents; Glutamates; Goals; Knowledge; Lead; Long-Term Effects; Longitudinal Studies; Male Adolescents; Measures; Mecamylamine; Mediating; Microdialysis; Nicotine; Nicotine Withdrawal; Nicotinic Antagonists; Nucleus Accumbens; Pharmacological Treatment; Population; Positioning Attribute; Procedures; Public Policy; Rattus; Regulation; Relative (related person); Research; Research Personnel; Rewards; Risk; Role; Sex Characteristics; Smoker; Smoking; Smoking Behavior; System; Teenagers; Tobacco; Ventral Tegmental Area; Withdrawal; Work; adolescent smoking; base; effective therapy; gamma-Aminobutyric Acid; health economics; in vivo; innovation; men' s group; neurochemistry; neuromechanism; neuronal cell body; preference; programs; sex; skills; smoking cessation; tobacco abuse; transmission process; treatment strategy

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.

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，但在调节青少年吸烟行为的机制方面存在严重的知识差距。我们的初步数据表明，与成年雄性大鼠相比，青春期雄性大鼠的尼古丁奖励增强，尼古丁戒断减少。该提案通过检查介导尼古丁奖励和戒断的行为影响中的发育敏感性和性别差异的神经机制来扩展我们之前的工作。为了研究青少年接触尼古丁所产生的长期后果，我们的建议还包括在青春期预先接触尼古丁的成年大鼠。尼古丁奖赏部分是通过增强伏隔核 (NAcc) 中的多巴胺 (DA) 传递来介导的。相反，尼古丁戒断会导致 NAcc DA 水平下降。 NAcc DA 传输的变化是由兴奋性和抑制系统介导的，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，而抑制性系统发育不全。我们假设相对于成年人，青少年会表现出更高的尼古丁奖励和更少的尼古丁戒断。这些发育差异可能是通过增强 VTA DA 细胞体的兴奋和减少抑制来介导的。总的来说，我们预计这些差异在女性青少年和尼古丁预先暴露的大鼠中会被放大。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更容易长期滥用烟草。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来比较 NAcc DA 以及尼古丁给药后和尼古丁戒断期间 VTA 中兴奋和抑制系统的伴随测量。这项研究意义重大，因为我们的研究结果可能对指导有关针对青少年和女性的烟草监管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机制将为年轻吸烟者提供更有效的治疗，因为他们最有可能患上长期吸烟引起的疾病。