Mechanisms of developmental sensitivity to nicotine withdrawal

对尼古丁戒断的发育敏感性机制

• 批准号: 7547212
• 负责人: LUIS ALBERTO NATIVIDAD
• 金额: $ 2.62万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-03 至 2011-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547212
• 关键词: Abstinence; Address; Adolescence; Adolescent; Adult; Affective; Agonist; Animals; Behavioral; Body Regions; Clinical Research; Development; Dopamine; Glutamate Agonist; Glutamates; Health; High Pressure Liquid Chromatography; Implant; Ipsilateral; Knowledge; Laboratories; Measures; Mecamylamine; Mediating; Microdialysis; Monitor; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Perfusion; Personal Satisfaction; Pharmaceutical Preparations; Procedures; Property; Pump; Rate; Rattus; Relative (related person); Research; Rodent; Role; Signal Transduction; Smoker; Smoking; Smoking Behavior; Staging; Synapses; System; Testing; Title; Ventral Tegmental Area; Withdrawal; adolescent smoking; age group; day; experience; gamma-Aminobutyric Acid; improved; in vivo; neurochemistry; neuronal cell body; neurotransmission; nicotine patch; response; smoking cessation; subcutaneous

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.

描述（由申请人提供）：本申请的目的是比较介导发展差异与尼古丁戒断的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避免了尼古丁戒断的负面后果。但是，目前尚不清楚尼古丁在青少年发展时期有多么有助于吸烟行为。这种知识差距提出了一个问题，因为目前的戒烟策略集中在减轻戒断，这些药物可能无效地治疗可能不会戒断的青少年吸烟者。这是由临床研究支持的，表明诸如尼古丁斑块之类的治疗方法不能提高年轻吸烟者的禁欲。这些发现以及长期吸烟产生的已知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。我们实验室中的动物研究表明，相对于成年人，青少年大鼠的身体和负面情感特性较低。但是，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，戒断的机制涉及伏隔核（NACC）的多巴胺水平降低，这是中麦盐多巴胺途径的末端区域。该途径起源于腹侧对接区域（VTA），其中多巴胺细胞体受抑制性γ-氨基丁酸（GABA）和兴奋性谷氨酸神经传递的严格调节。几项研究线表明，抑制性GABA系统的发育不足，并且在青春期期间兴奋性谷氨酸系统过于发达。我们认为，青少年缺乏尼古丁戒断与NACC多巴胺水平的降低有关，这将是由于抑制性降低（即较小的GABA活性）和增强的激发（即增加谷氨酸活性）在VTA相对与成年大鼠相对的多巴胺细胞体区域的抑制作用（即更多的谷氨酸活性）。我们的假设将通过使用体内微透析和高性能液相色谱法来比较青少年和成年大鼠的NaCC多巴胺和伴随VTA GABA和谷氨酸水平的措施，并经历了烟碱戒断。此外，我们将利用药理学方法来表征VTA GABA和谷氨酸在介导青春期和成年大鼠中尼古丁戒断的神经化学作用中的作用。总的来说，这些研究将提供介导啮齿动物发育不同阶段尼古丁戒断的机制的特征。