Behavioral Sensitization to Nicotine--Relevance to Neuroprotection

对尼古丁的行为敏感性——与神经保护的相关性

• 批准号: 6666474
• 负责人: P. A. Ferchmin
• 金额: $ 14.82万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666474
• 关键词: behavioral habituation /sensitization; biological signal transduction; chemosensitizing agent; cooperative study; diterpenes; drug interactions; laboratory rat; marine biology; messenger RNA; minority institution research support; mixed tissue /cell culture; neuropharmacology; neuroprotectants; neurotoxicology; neurotrophic factors; nicotine; nicotinic receptors; nitric oxide; behavioral habituation /sensitization; biological signal transduction; chemosensitizing agent; cooperative study; diterpenes; drug interactions; laboratory rat; marine biology; messenger RNA; minority institution research support; mixed tissue /cell culture; neuropharmacology; neuroprotectants; neurotoxicology; neurotrophic factors; nicotine; nicotinic receptors; nitric oxide

Despite the well known addictive and harmful effects of nicotine, epidemiological and experimental studies have shown that nicotine is neuroprotective. Specific schedules of nicotine administration produce different behavioral and physiological effects. We propose that this distinct behavioral and physiological states correspond to different degrees or modes of nicotine-mediated neuroprotection. To test this hypothesis, the susceptibility to neural injury will be assessed in brain slices from rats subjected to various nicotine pretreatments. The injury will be induced by N-methyl-D-aspartate (NMDA), a drug that induces stroke-like neural damage. Besides nicotine, cigarette smoke contains many compounds of unknown activity, including cyclic terpenoid5 called cembranoids. Our group discovered that cembranoids from Puerto Rico marine organisms, as well as those from tobacco, inhibit neuronal nicotinic receptors and also are capable of modifying the behavioral effects of nicotine. In the present project cembranoid effect on the behavioral and neuroprotective effects of nicotine will be analyzed. Signal transduction pathways involved in nicotine-induced neuroprotection, will be studied in pure and mixed cultures of hippocampal cells. mRNA differential display will be performed to search for genes whose expression is induced by nicotine treatment. In addition, the role of nitric oxide and neurotrophins will be assessed. These experiments will be done in collaboration with the group of Dr. Jean De Vellis at the University of California Los Angeles.

尽管尼古丁具有众所周知的成瘾和有害作用，但流行病学和实验研究表明尼古丁是神经保护性的。尼古丁给药的特定时间表会产生不同的行为和生理影响。我们建议这种独特的行为和生理状态对应于尼古丁介导的神经保护的不同程度或模式。为了检验这一假设，将在接受各种尼古丁预处理的大鼠切片中评估对神经损伤的敏感性。损伤将由N-甲基-D-天冬氨酸（NMDA）诱导，该药物会诱导中风样神经损伤。除尼古丁外，香烟烟雾还含有许多未知活性的化合物，包括循环萜类化合物，称为摄氏脑植物。我们的小组发现，来自波多黎各海洋生物的核植物以及烟草的生物体抑制神经元烟碱受体，并且能够改变尼古丁的行为效应。在目前的项目中，将分析对尼古丁的行为和神经保护作用的核心效应。将在海马细胞的纯和混合培养物中研究参与尼古丁诱导的神经保护的信号转导途径。将执行mRNA差异显示，以搜索尼古丁治疗诱导表达的基因。另外，将评估一氧化氮和神经营养蛋白的作用。这些实验将与加利福尼亚大学洛杉矶分校的让·德·韦利斯博士合作进行。