Nicotine, a major ingredient in tobacco smoke, readily penetrates the central nervous system and produces marked psychopharmacological, behavioral and neurochemical effects. We have previously observed that nicotine acts to release dopamine from dopaminergic neurons in the striatum by two mechanisms, one seen at low concentrations and the other at high concentrations of the drug. When animals are exposed chronically to nicotine, there is an attenuation of the nicotine-induced release of dopamine. The present experiments represent a logical expansion of our current research efforts to gain a better understanding of the actions and mechanism of action of nicotine in the mammalian central nervous system. A series of biochemical and pharmacological experiments have been designed: First, we will investigate the effect of acute and chronic nicotine administration on dopamine neurotransmission in vivo. Experiments will be carried out using push-pull cannula perfusion techniques to measure the nicotine-induced release of dopamine from striatal tissue in freely moving unanesthetized rats. Experiments will be conducted in animals that have been chronically exposed to nicotine agonists administered from Alzet minipumps for 7, 14 and 28 days and/or 3 or 6 months. Secondly, we will determine the mechanism of the attenuation of the nicotine-induced release of dopamine from striatum of rats treated chronically with nicotine. It will be determined if there is an alteration in nicotinic receptors assessed by ligand binding studies or some other aspect of dopamine neurodynamics (decreased dopamine levels, alteration in dopamine synthesis, a release of newly synthesized dopamine). Third, we will determine the intracellular mechanism of action by which activation of nicotinic-cholinergic receptors release dopamine from the striatum. Specifically, the role of cAMP or Na+-K+-ATPase will be assessed. Fourth, we will attempt to come to an understanding of the modulation of the nicotine-induced release of dopamine by examining the effect of substance P, ATP, adenosine or histamine on the nicotine-induced release of dopamine. Finally, we will determine the effect of nicotine on dopamine neurotransmission as a function of age. These experiments should provide extremely valuable information on the chronic effects of nicotine on dopamine transmission, on the mechanism of this action and the mechanism of tolerance to the nicotine-induced release of dopamine from normal and aged animals. These studies will also be of most importance since chronic studies should correlate better with the way the drug is used by the human population.
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