Behavioral Sensitization to Nicotine--Relevance to Neuroprotection

尽管尼古丁的成瘾性和有害作用众所周知，但流行病学和实验研究表明，尼古丁具有神经保护作用。尼古丁给药的特定时间表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。为了检验这一假设，将在接受各种尼古丁预处理的大鼠脑切片中评估对神经损伤的易感性。损伤将由N-甲基-D-天冬氨酸（NMDA）诱导，NMDA是一种诱导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，包括称为西松烷的环萜类化合物。我们的研究小组发现，来自波多黎各海洋生物的西松烷类化合物以及来自烟草的西松烷类化合物抑制神经元烟碱受体，并且还能够改变尼古丁的行为效应。在本项目中，将分析西松烷类化合物对尼古丁的行为和神经保护作用的影响。尼古丁诱导的神经保护的信号转导途径，将在纯和混合培养的海马细胞进行研究。将进行mRNA差异显示以寻找其表达被尼古丁处理诱导的基因。此外，还将评估一氧化氮和神经营养因子的作用。这些实验将与加州洛杉矶大学的Jean De Vellis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.