Mechanisms of developmental sensitivity to nicotine withdrawal

描述(申请人提供)：本申请的目的是比较调节发育差异的神经化学机制和尼古丁戒断对行为的影响。众所周知，成年人的吸烟行为在很大程度上是通过避免尼古丁戒断的负面后果来调节的。然而，目前尚不清楚尼古丁戒断对青少年发育期吸烟行为的影响。这一认识差距带来了一个问题，因为目前的戒烟策略侧重于缓解戒烟，而这些药物在治疗可能没有戒烟经历的青少年吸烟者方面可能无效。临床研究表明，尼古丁贴片等疗法并不能提高年轻吸烟者的戒烟率，这一点得到了临床研究的支持。这些发现以及长期吸烟产生的已知健康并发症强调了调查尼古丁戒断在青少年吸烟行为中的作用的重要性。我们实验室的动物研究表明，与成年大鼠相比，青春期大鼠表现出较少的生理和尼古丁戒断的负面情感特征。然而，调节这些行为差异的神经化学机制尚不清楚。神经化学研究表明，戒断的机制与伏隔核(NAcc)多巴胺水平下降有关，NAcc是中脑边缘多巴胺通路的末端区域。这条通路起源于腹侧被盖区(VTA)，在那里，多巴胺胞体受到抑制性γ-氨基丁酸(GABA)和兴奋性谷氨酸神经传递的严格调控。一些研究表明，抑制性GABA系统不发达，兴奋性谷氨酸系统在青春期过度发育。我们认为，青少年缺乏尼古丁戒断与NAcc多巴胺水平下降较少有关，这将是由于与成年大鼠相比，VTA的多巴胺细胞体区域的抑制减少(即GABA活性减少)和兴奋增加(即谷氨酸活性增加)。我们的假设将通过体内微透析和高效液相色谱来验证，以比较NAcc、多巴胺以及伴随而来的VTA、GABA和谷氨酸水平在经历尼古丁戒断的青少年和成年大鼠中的水平。此外，我们将利用药理学方法来表征VTA、GABA和谷氨酸在青少年和成年大鼠尼古丁戒断的神经化学效应中的作用。总而言之，这些研究将提供在啮齿动物发育的不同阶段调节尼古丁戒断的机制的特征。

DESCRIPTION (provided by applicant): The objective of this application is to compare the neurochemical mechanisms mediating developmental differences to the behavioral effects of nicotine withdrawal. It is well established that adult smoking behavior is mediated in large part by avoiding the negative consequences of nicotine withdrawal. However, it is presently not clear how nicotine withdrawal contributes to smoking behavior during the adolescent period of development. This knowledge gap presents a problem because current smoking cessation strategies focus on alleviating withdrawal and these medications may be ineffective in treating adolescent smokers who may not experience withdrawal. This is supported by clinical studies showing that treatments such as the nicotine patch do not improve abstinence rates in young smokers. These findings along with the known health complications produced by long-term smoking underscore the importance of investigating the role of nicotine withdrawal in adolescent smoking behavior. Animal studies in our laboratory demonstrated that adolescent rats display less physical and negative affective properties of nicotine withdrawal relative to adults. However, the neurochemical mechanisms that mediate these behavioral differences are unclear. Neurochemical studies have shown that the mechanisms of withdrawal involve decreases in dopamine levels in the nucleus accumbens (NAcc), a terminal region of the mesolimbic dopamine pathway. This pathway originates in the ventral tegmental area (VTA) where dopamine cell bodies are tightly regulated by inhibitory gamma- aminobutyric acid (GABA) and excitatory glutamate neurotransmission. Several lines of research have suggested that inhibitory GABA systems are underdeveloped and excitatory glutamate systems are overdeveloped during adolescence. We propose that a lack of nicotine withdrawal in adolescents is related to fewer decreases in NAcc dopamine levels, and this will be due to reduced inhibitory (i.e., less GABA activity) and enhanced excitation (i.e., more glutamate activity) in the dopamine cell body region of the VTA relative to adult rats. Our hypothesis will be examined by using in vivo microdialysis and high performance liquid chromatography to compare NAcc dopamine and concomitant measures of VTA GABA and glutamate levels in adolescent and adult rats experiencing nicotine withdrawal. In addition, we will utilize pharmacological approaches to characterize the role of VTA GABA and glutamate in mediating the neurochemical effects of nicotine withdrawal in adolescent and adult rats. Collectively, these studies will provide a characterization of the mechanisms that mediate nicotine withdrawal at different stages of rodent development.