Behavioral Sensitization to Nicotine--Relevance to Neuroprotection

尽管众所周知，尼古丁具有成瘾和有害作用，但流行病学和实验研究表明，尼古丁具有神经保护作用。尼古丁给药的具体时间表会产生不同的行为和生理效果。我们认为，这种不同的行为和生理状态对应于不同程度或模式的尼古丁介导的神经保护。为了验证这一假设，将评估接受不同尼古丁预处理的大鼠脑片对神经损伤的敏感性。这种损伤将由N-甲基-D-天冬氨酸(NMDA)诱导，这是一种导致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未知活性的化合物，其中包括被称为西膜类化合物的环状萜类化合物。我们的团队发现，来自波多黎各海洋生物以及来自烟草的西膜类化合物，可以抑制神经性尼古丁受体，也能够改变尼古丁的行为效应。在本项目中，将分析西膜激素对尼古丁的行为和神经保护作用的影响。涉及尼古丁诱导的神经保护的信号转导通路，将在海马细胞的纯培养和混合培养中进行研究。将进行mRNA差异显示，以寻找尼古丁处理诱导表达的基因。此外，还将评估一氧化氮和神经营养因子的作用。这些实验将与加州大学洛杉矶分校的Jean de Vellis博士团队合作完成。

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.