Nicotine acetylcholine receptors (nAChRs) are present throughout the central nervous system and have been implicated in a number of normal physiological functions including central control of respiratory, cardiovascular and gastrointestinal function. These receptors, of which there are multiple subtypes, are pentameric structures and are structurally confirmed into ligand-gated ion channels with a diverse pharmacology and function. For this proposal, our overall objective is to investigate the role of nAChRs in brainstem respiratory control groups (RCGs) . The central hypothesis is that nicotinic subunits are differentially expressed in respiratory centers where they serve to modulate respiratory neuronal function, and that changes in nAChR functional expression will alter the cellular responses in brainstem respiratory neurons. To this end, we are proposing the following specific aims: 1) To identify the cellular distribution and measure the density of nicotinic acetylcholine receptor subtypes in the brainstem respiratory control groups, 2) To establish the response of brainstem neurons to acute and chronic nicotine exposure 3) To establish the effects of acute and chronic nicotine exposure on brainstem function. We will initiate these studies by focusing on identifying and characterizing the nicotinic receptors present in the pontine and medullary (dorsal and ventral) respiratory groups (PRG, DRG, VRG) and to determine the mechanism by which chronic nAChR activation compromises the integrity and function in these respiratory pathways. The proposed work will serve as the basis for understanding the role nAChRs play in normal respiratory physiology. We will also be able to demonstrate the effects of nicotine on RCG's nAChRs and correlate them with changes in total DNA, cellular density, and cell viability. We will use molecular methods to identify the various nicotinic receptor subtypes and new pharmacological tools, including radioligands, to determine their tissue specific expression and density. These results will also be significant in that they may serve as the foundation for the development and adult respiratory disorders which are bound to increase significantly in the future due to the steady increase in the incidence of smoking, particularly among young females of child bearing age.
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