Nicotine, the primary addictive substance in tobacco, induces profound behavioral changes; but the underlying mechanisms are not well understood. The long-term goal of our research is to understand the mechanisms of nicotine-induced behaviors in a genetically tractable model organism. The nematode C. elegans has recently emerged as a popular model organism for the study of various phenomena in neurobiology including substance dependence (also called drug addiction), because of its amenability to genetic manipulation and very well characterized nervous system. Here, we have developed a C. elegans model of nicotine dependence. We show that nicotine induces profound behavioral responses in C. elegans that mimic those observed in mammals. Importantly, we find that genes and pathways regulating nicotine dependence in mammals are functionally conserved in C. elegans, including nicotinic acetylcholine receptors (nAChRs, the molecular target of nicotine) and dopamine-mediated neurotransmission. We have also identified a TRP channel protein as a novel player critical for nicotine-induced behaviors. In this proposal, we will elucidate the mechanisms by which nAChRs, dopamine transmission and TRP channel regulate nicotine-induced behaviors. To do so, we will take a multidisciplinary approach involving behavioral analysis, pharmacology and genetics. Nicotine dependence is a worldwide health problem and represents the leading preventable cause of death in the United States. About one-third of adults in the world are smokers, and the number of smokers in developing countries is still on the rise. As the genes and pathways that we propose to study are highly conserved throughout phylogeny, our research will provide novel insights into our understanding of the mechanisms of nicotine dependence not only in worms, but also in humans. This study may lead to the identification of novel therapeutic targets for treating tobacco dependence in humans. ? ? ?
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