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Prolonged exposure to nicotine causes long-lasting and specific inactivation of nicotinic receptor activity in brain neurons, a process though to underlie nicotine addiction. At present, the molecular basis for nicotine adaptation is almost completely unknown. We have begun using a genetic approach to identify molecules required for nicotine adaptation in the nematode C. elegans. Nematode egg-laying behavior undergoes a process of long-term adaptation to nicotine that is similar in many respects to nicotine adaptation in vertebrates. We have found that in C. elegans, prolonged nicotine treatment results in long-term adaptation of nicotinic receptors that control egg-laying. In naive animals, acute exposure to cholinergic agonists led to the efficient stimulation of egg-laying, a response mediated by a nicotinic receptor functionally expressed in both neurons and muscle cells. Overnight exposure to nicotine led to a specific and long-lasting change in egg-laying behavior, which rendered the nicotine-adapted animals insensitive to simulation of egg-laying by nicotinic agonist. Genetic screens conducted in our laboratory have identified a number of adaptation defective mutants, which define several genes that are essential for adaptation to nicotine. For example, mutant animals defective in the gene tpa-1, which encodes a homologue of protein kinase C (PKC), failed to undergo adaptation to nicotine, and remained sensitive to cholinergic agonists even after long nicotine exposure. Long treatments with phorbol esters also inhibited the acute response to cholinergic agonists in a tpa-1 dependent manner. These results suggest that nicotine adaptation may involve long-term inactivation of nicotinic receptors by PKC.
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