The long-term objective of these studies is to understand the effect that nicotine has on nicotinic cholinergic receptor function in the brain. These effects are very likely directly related to the addictive properties of nicotine and thus to the health consequences of smoking. In the proposed studies the function of brain nicotinic cholinergic receptors will be studied in vivo in the rat by measuring nicotine-induced prolactin release. The hypothesis to be tested is that chronic administration of nicotine inactivates nicotinic receptors and thus acts an allosteric antagonist. The desensitization of nicotinic receptors by a single injection of nicotine and the inactivation of these receptors by chronic administration of nicotine will then be assessed with regard to time-course, dose-response relationship, and protection by nicotinic antagonists. The effects of chronic treatment with nicotine will then be compared to treatment with cholinesterase inhibitors, which increase receptor stimulation by acetylcholine. Differences in the effects of these two treatments on receptor function may be related to fundamental differences in the binding of nicotine and acetylcholine at the receptor, and this will be studied by measuring the temperature dependence of the kinetics of binding of [3H] acetylcholine and [3H] (-) nicotine to the receptor. The molecular mechanisms underlying desensitization and inactivation of brain nicotinic receptors will be studied by determining whether the receptor in brain is a substrate for phosphorylation/dephosphorylation mechanisms, as it is in peripheral tissues, and whether the phosphorylation state of the receptor is related to its function. Studies of the mRNA coding for nicotinic receptor alpha and beta subunits will determine whether the increased density of receptors that follows chronic nicotine treatment is accompanied by increased synthesis of message for receptor, and for which subtype. The effects of chronic nicotine on nicotinic receptor mediated release of neurotransmitters in the striatum, n. accumbens, and hippocampus will be assessed to determine the generality of the inactivation phenomenon.
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