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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009457-04
Application #
2733552
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1995-07-01
Project End
1999-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Freund, Ronald K; Graw, Sharon; Choo, Kevin S et al. (2016) Genetic knockout of the ?7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner. Neurosci Lett 627:1-6
Sinkus, Melissa L; Graw, Sharon; Freedman, Robert et al. (2015) The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. Neuropharmacology 96:274-88
Stephens, Sarah H; Franks, Alexis; Berger, Ralph et al. (2012) Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia. Psychiatr Genet 22:1-14
Neeley, Eric W; Berger, Ralph; Koenig, James I et al. (2011) Strain dependent effects of prenatal stress on gene expression in the rat hippocampus. Physiol Behav 104:334-9
Schulz, Kalynn M; Pearson, Jennifer N; Neeley, Eric W et al. (2011) Maternal stress during pregnancy causes sex-specific alterations in offspring memory performance, social interactions, indices of anxiety, and body mass. Physiol Behav 104:340-7
Finlay-Schultz, Jessica; Canastar, Andrew; Short, Margaret et al. (2011) Transcriptional repression of the ?7 nicotinic acetylcholine receptor subunit gene (CHRNA7) by activating protein-2? (AP-2?). J Biol Chem 286:42123-32
Neeley, E W; Berger, R; Koenig, J I et al. (2011) Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains. Neuroscience 187:24-35
Sinkus, Melissa L; Wamboldt, Marianne Z; Barton, Amanda et al. (2011) The ?7 nicotinic acetylcholine receptor and the acute stress response: maternal genotype determines offspring phenotype. Physiol Behav 104:321-6
Araud, Tanguy; Graw, Sharon; Berger, Ralph et al. (2011) The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of ?7*nAChR function. Biochem Pharmacol 82:904-14
Mexal, Sharon; Berger, Ralph; Logel, Judy et al. (2010) Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. J Mol Neurosci 40:185-95

Showing the most recent 10 out of 37 publications