In 1988, the US Surgeon General concluded that tobacco products are addictive and nicotine is the main pharmacological agent in tobacco responsible for tobacco's addictive nature. Despite over whelming evidence of the adverse health effects of smoking, it is estimated that 68.8 million Americans use tobacco products and 400,000 tobacco-related deaths occur in the United States each year. However, it is not completely understood why nicotine is addictive. One reason for this incomplete understanding of nicotine addiction may be that addiction is a complex disorder with many factors contributing to the disease. Possible factors that may contribute to nicotine addiction include genetics and learning. Many studies suggest that nicotine enhances learning. Specifically, the limbic area of the brain is involved in both learning and addiction and thus nicotine effects on this area may mediate cognitive influences on addiction. It is the hypothesis of this proposal that nicotine alters the function of the hippocampus during learning, producing a learned state that is different from learning in the absence of the drug, and that this learning may involve different patterns of cell signaling and gene activation than those activated during comparable learning without drug. The ability of nicotine to enhance learning processes may facilitate addiction by contributing to drug-context associations that could precipitate craving and relapse. In support of this, nicotine has been shown to enhance a long-lasting form of contextual fear conditioning, a type of classical conditioning that involves the hippocampus. Long-term memory storage is known to involve alteration in gene expression, and the proteins encoded by these induced genes, such as MAP kinases, result in long-lasting changes in neuronal function. Nicotine can also alter activation of MAP kinases. Proposed experiment will identify the nicotinic acetylcholinergic receptor subtypes, identify the neural site of action, and identify MAP kinases involved in the long-lasting enhancement of contextual fear conditioning by nicotine. Investigating the effects of nicotine on learning from the level of receptor activation to changes in cell signaling will enhance understanding of addiction and aid in development of treatments for nicotine addiction ? ?
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