THE UPREGULATION OF NICOTINIC RECEPTORS

烟碱受体的上调

• 批准号: 7287655
• 负责人: WILLIAM GREEN
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287655
• 关键词: Affect; Affinity; Agonist; Antibodies; Behavioral; Binding; Binding Sites; Biochemistry and Pharmacology Cancer Activity; Biological Assay; Brain; Brain region; Cell Line; Cell surface; Cessation of life; Chemicals; Chimera organism; Chronic; Collaborations; Consensus; Data; Dependence; Exposure to; Goals; Health; Health Care Costs; Laboratories; Link; Long-Term Potentiation; Measures; Methods; Molecular Biology; Molecular Conformation; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Numbers; Pharmacology; Post-Translational Protein Processing; Radio; Rattus; Research; Research Personnel; Role; Shapes; Signal Pathway; Specificity; Surface; System; Testing; Time; Tobacco; Tobacco smoking; United States; Up-Regulation; Ventral Tegmental Area; addiction; dopaminergic neuron; drug of abuse; in vivo; programs; receptor; receptor function; receptor upregulation; research study; response; trafficking

Tobacco smoking is a major health problem leading each year to $50 billion dollars in health costs and 400,000 deaths in the United States. Significant evidence indicates that nicotine is the component in tobacco leading to abuse and addiction. Nicotine binds to nicotinic receptors found in the brain. To characterize the molecular biology of nicotine addiction, our research will focus on nicotinic receptors in the brain and how nicotine-induced changes in nicotinic receptors correlates with aspects of addiction. Like other drugs of abuse, many of the addictive effects of nicotine appear to result from the stimulation of dopaminergic, mesolimbic neurons, in particular dopaminergic neurons from the ventral tegmental area (VTA). The short-term effects of nicotine are caused by the activation of nicotinic receptors on these neurons. Long-term exposure to nicotine enhances or "sensitizes" the response of these neurons to nicotine, which correlates with the enhancement or "upregulation" of high-affinity binding to nicotinic receptors. The goals of this proposal are: 1) to identify nicotinic receptor subtypes involved in nicotine upregulation, 2) to identify mechanisms involved in nicotine upregulation of different nicotinic receptor subtypes and 3) to test whether nicotinic receptor upregulation by nicotine is involved in nicotine-induced long-term potentiation and behavorial/chemical sensitization as a collaboration with Projects 2 and 3. The hypotheses to be tested are that: 1) nicotinic receptor upregulation in heterologous expression systems and in vivo is caused by a receptor state change that causes the receptors to enter a hypersensitive or functionally upregulated state; 2) nicotine-induced long-term potentiation and sensitization of the nicotine response are initiated, at least in part, by receptor upregulation. Several possible nicotinic subunit combinations will be expressed to test whether upregulation occurs for each combination and the extent to which upregulation is a change in receptor number or entry into a hypersensitive state. Additional experiments will assay for nicotinic receptor upregulation in brain after nicotine exposure in rats. These experiments will test whether nicotine exposure, which induces locomotor sensitization, causes nicotinic receptor upregulation in the brain regions identified with locomotor sensitization and examine which nicotinic receptor subtypes are upregulated in these brain regions.

吸烟是一个主要的健康问题，每年导致500亿美元的健康成本， 美国有40万人死亡。大量证据表明，尼古丁是烟草中的一种成分， 导致滥用和成瘾。尼古丁与大脑中的烟碱受体结合。表征 尼古丁成瘾的分子生物学，我们的研究将集中在大脑中的尼古丁受体，以及如何 烟碱诱导的烟碱受体的变化与成瘾的各个方面相关。 像其他滥用药物一样，尼古丁的许多成瘾作用似乎是由刺激 多巴胺能中脑边缘神经元，特别是来自腹侧被盖区的多巴胺能神经元 （VTA）。尼古丁的短期效应是由这些细胞上的烟碱受体激活引起的。 神经元长期暴露于尼古丁增强或“敏感”这些神经元的反应， 尼古丁，其与尼古丁的高亲和力结合的增强或“上调”相关。 受体。本研究的目标是：1）鉴定尼古丁受体亚型， 上调，2）鉴定参与不同烟碱受体的烟碱上调的机制 亚型和3）测试尼古丁引起的烟碱受体上调是否涉及尼古丁诱导的细胞凋亡。 与项目2和项目3合作开展长期增效和杀虫剂/化学增敏。的 待检验的假设是：1）异源表达系统中烟碱受体上调， 在体内是由受体状态变化引起的，该变化导致受体进入超敏或 功能上调状态; 2）尼古丁诱导的尼古丁长时程增强和敏化 应答至少部分是通过受体上调而启动的。几种可能的烟碱亚基 将表达组合以测试每种组合是否发生上调以及上调的程度。 所述上调是受体数量的变化或进入过敏状态。额外 实验将测定大鼠暴露于尼古丁后大脑中尼古丁受体的上调。这些 实验将测试尼古丁暴露是否会引起运动敏化， 受体上调的大脑区域确定与运动敏化，并检查哪些尼古丁 受体亚型在这些脑区域中上调。