Recognition by the Surgeon General that individuals differ in their avidity for and responses to tobacco *USDA), 1988) implies that there could be heritable differences determining human smoking habits. Variability in gene expression, due to genetic differences in the human population, may determine differences in observed behaviors or physiological responses to environmental effectors, including smoking. Studies of monozygotic and dizygotic twins suggest that the incidence of smoking in both twins is higher among the identical twin pairs, as well as continuance of the smoking habit. Animal models (mouse) of nicotine sensitivity indicate that approximately 35-40% of the variance in initial response to nicotine in different mouse strains is due to differences in the number and distribution of nicotinic receptors in the brain. Tolerance or addiction to nicotine in humans may, thus, be related to individual differences in the nicotinic acetylcholine receptor family. This gene family is complex and subunits are known to exist in variable combinations with different affinities for nicotine, differences which could relate to function in determining whether a person becomes addicted to tobacco use or not. The proposed studies will test the hypothesis that variability in nicotinic receptor expression or function exists in human postmortem brain and that these differences can be correlated with smoking history. We will measure the regional binding for the nicotinic receptor family in postmortem brain of smokers and non smokers, characterize the regional expression of mRNA for three nicotinic receptor subunits and determine the regional functional status of these receptors. Correlating results from this study with the subjects' smoking history in life, will provide new information concerning the importance of this receptor family in nicotine addiction.
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