Tobacco smoking is a major health problem leading each year to $50 billion dollars in health costs and 400,000 deaths in the United States. Significant evidence indicates that nicotine is the component in tobacco leading to abuse and addiction. Nicotine binds to nicotinic receptors found in the brain. To characterize the molecular biology of nicotine addiction, our research will focus on nicotinic receptors in the brain and how nicotine-induced changes in nicotinic receptors correlates with aspects of addiction. Like other drugs of abuse, many of the addictive effects of nicotine appear to result from the stimulation dopaminergic, mesolimbic neurons, in particular dopaminergic neurons from the ventral tegmental area (VTA). The short-term effects of nicotine are caused by the activation of nicotinic receptors on these neurons. Long-term exposure to nicotine enhances or """"""""sensitizes"""""""" the response of these neurons to nicotine, which correlates with the enhancement or """"""""upregulation"""""""" of high-affinity binding to nicotinic receptors. The goals of this application are: 1) to identify receptor subtypes involved in nicotine upregulation, 2) to identify the mechanisms that cause nicotine upregulation of nicotinic receptors and 3) to test whether nicotinic receptor upregulation by nicotine is involved in the sensitization of the response to nicotine. The hypotheses to be tested are that: 1) at nicotine concentrations achieved during smoking, the upregulation of nicotinic receptors is primarily an upregulation of alpha4beta2-containing receptors; 2) nicotinic receptor upregulation in vivo is caused by a receptor state change that causes the receptors to enter a hypersensitive state; 3) sensitization of the nicotine response of VTA neurons is caused, at least in part, by receptor upregulation. Several possible nicotinic subunit combinations will be expressed to test whether upregulation occurs for each combination and the extent to which upregulation is a change in receptor number or entry into a hypersensitive state. After, the experiment will be extended to cells expressing """"""""native"""""""" nicotinic receptors of unknown subunit composition, including PC12 rat pheochromocytoma cells, mouse N1E-115 neuroblastoma cells, and VTA neurons.
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