Behavioral Sensitization to Nicotine--Relevance to Neuroprotection

尽管众所周知尼古丁的成瘾性和有害作用，但流行病学和实验研究表明尼古丁具有神经保护作用。特定的尼古丁给药时间表会产生不同的行为和生理效应。我们认为，这种不同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。为了验证这一假设，我们将在接受各种尼古丁预处理的大鼠的大脑切片中评估神经损伤的易感性。这种损伤将由n -甲基- d -天冬氨酸（NMDA）引起，这是一种引起中风样神经损伤的药物。除了尼古丁，香烟烟雾中还含有许多活性未知的化合物，包括被称为类膜类的环萜。我们的研究小组发现，来自波多黎各海洋生物的类膜生物，以及来自烟草的类膜生物，能抑制神经元尼古丁受体，也能改变尼古丁对行为的影响。本项目将分析类胶质物质对尼古丁行为和神经保护作用的影响。信号转导通路涉及尼古丁诱导的神经保护，将在海马体细胞的纯和混合培养中进行研究。通过mRNA差异展示来寻找尼古丁诱导表达的基因。此外，将评估一氧化氮和神经营养素的作用。这些实验将与加州大学洛杉矶分校的让·德·韦利斯博士小组合作完成。

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.