THE UPREGULATION OF NICOTINIC RECEPTORS

吸烟是一个主要的健康问题，每年导致500亿美元的医疗成本和 美国有40万人死亡。大量证据表明，尼古丁是烟草中的成分。 导致滥用和上瘾。尼古丁与大脑中发现的尼古丁受体结合。要刻画 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及其如何 尼古丁诱导的尼古丁受体的变化与成瘾的某些方面有关。 像其他滥用药物一样，尼古丁的许多成瘾作用似乎是由于刺激 多巴胺能、中脑边缘神经元，特别是腹侧被盖区的多巴胺能神经元 (VTA)。尼古丁的短期效应是由尼古丁受体在这些细胞上激活引起的。 神经元。长期暴露于尼古丁可增强或“敏化”这些神经元对 尼古丁，它与尼古丁高亲和力结合的增强或上调有关 感受器。这项提议的目标是：1)识别尼古丁中涉及的尼古丁受体亚型 上调，2)确定不同尼古丁受体上调尼古丁的机制 3)测试尼古丁对尼古丁受体的上调是否参与尼古丁诱导的 长期增强和行为/化学敏化作为与项目2和3的协作。 有待检验的假设是：1)烟碱受体在异源表达系统和 在体内是由受体状态的变化引起的，这种变化导致受体进入过敏性或 功能上调状态；2)尼古丁诱导的长时程增强和尼古丁敏化 反应至少部分是由受体上调引起的。几种可能的烟碱亚单位 将表示组合，以测试每个组合是否发生上调，以及 这种上调是受体数量的变化或进入超敏感状态。其他内容 实验将检测尼古丁暴露后大鼠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导致尼古丁产生运动敏感化。 运动敏感区的受体上调，并检查哪种尼古丁 受体亚型在这些脑区上调。

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.