The development of tolerance to nicotine parallels, and may be causally linked to the development of dependent smoking behavior. Understandably, considerable attention has been given to identifying the mechanisms underlying tolerance. Research has focused on kinetic changes in drug distribution, or on cellular nervous system changes in receptor sensitivity. However, we have demonstrated a third factor, namely, that learned associations with environmental cues predicting nicotine delivery can powerfully contribute to the tolerance process. Thus tolerance to intermittent nicotine exposure can include """"""""associative"""""""" (learned) and """"""""nonassociative"""""""" components, and both must be considered if the tolerance process, and its contribution to smoking behavior, are to be thoroughly understood. Our current research is designed to better identify the mechanisms of conditioned tolerance. Using nicotine-induced antinociception and activation of the hypothalamic-pituitary-adrenocortical system (HPA) in laboratory rats as models, we propose to more systematically investigate the mechanisms of conditioned tolerance. Our strategy in Experiments 1-4 will be to first clarify the levels of the nervous system where nicotine acts acutely to produce its effects. This will be accomplished by combining central- vs peripheral-nervous system stimulation of nicotinic-cholinergic systems with selective central vs peripheral pharmacological blockade to better identify where nicotine is acting to produced its antinociceptive and HPA effects. Exploiting the results and methods of Experiment 1-4 on the location of nicotine's action and using an established paradigm for distinguishing associative from nonassociative tolerance, we will continue to ask -- in the remaining studies of this proposal -- the fundamental questions of this research program: what is being conditionally released to reduce nicotine responsiveness and where is it acting?
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