Mechanisms of developmental sensitivity to nicotine withdrawal

描述（由申请人提供）：本申请的目的是比较尼古丁戒断对发育差异和行为影响的神经化学机制。众所周知，成人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如何影响青少年时期的吸烟行为。这一知识差距带来了一个问题，因为目前的戒烟策略侧重于减轻戒断反应，而这些药物可能对没有戒断反应的青少年吸烟者无效。临床研究表明，诸如尼古丁贴片之类的治疗方法并不能提高年轻吸烟者的戒断率。这些发现以及已知的长期吸烟引起的健康并发症强调了研究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，与成年鼠相比，青春期大鼠表现出较少的尼古丁戒断的身体和负面情感特性。然而，介导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，戒断的机制涉及中边缘多巴胺通路末端区域伏隔核（NAcc）多巴胺水平的降低。该通路起源于腹侧被盖区（VTA），多巴胺细胞体受到抑制性γ -氨基丁酸（GABA）和兴奋性谷氨酸神经传递的严格调节。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达。我们提出，青少年缺乏尼古丁戒断与NAcc多巴胺水平下降较少有关，这将是由于相对于成年大鼠，VTA多巴胺细胞体区域的抑制性降低（即GABA活性降低）和兴奋性增强（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检验，以比较尼古丁戒断的青春期和成年大鼠的NAcc多巴胺和伴随的VTA、GABA和谷氨酸水平。此外，我们将利用药理学方法来表征VTA、GABA和谷氨酸在青春期和成年大鼠尼古丁戒断的神经化学效应中的作用。总的来说，这些研究将提供在啮齿动物发育的不同阶段介导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.