Studies carried out with human subjects have repeatedly demonstrated that genetic factors play a major role in regulating why some people smoke, and others do not. Other studies have demonstrated that sensitivity to the toxic actions of nicotine plays a major role in determining who smokes. Sensitivity to toxic actions also affects daily tobacco intake of smokers; smokers decrease tobacco intake when toxic responses develop. Previous studies funded by this grant have used the mouse to determine that genetically determined variations in nicotinic receptor genes regulate differences in initial sensitivity to nicotine. We have also shown that genetic factors influence the development of tolerance to nicotine following chronic treatment. The studies outlined in the first specific aim of this competing renewal application will use several nicotinic receptor subunit gene knockout (null mutant) mouse strains to identify the subunit compositions of native (naturally occurring) neuronal nicotinic receptors that are measured with several binding and functional assays. Studies outlined in the second specific aim will use these null mutant mice to determine the effects of chronic treatment with nicotine (multiple doses will be tested) on the number and functions of several nAChR subtypes. The relationships between chronic nicotine-induced changes in receptor numbers and function and altered behavioral responses to nicotine will be determined. These studies will provide a broader understanding of nicotinic receptor mediated mechanisms that modulate the development of tolerance, and perhaps sensitization, to behavioral responses produced by nicotine. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003194-22
Application #
6819887
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Satterlee, John S
Project Start
1983-09-30
Project End
2009-04-30
Budget Start
2004-07-15
Budget End
2005-04-30
Support Year
22
Fiscal Year
2004
Total Cost
$322,604
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Semenova, Svetlana; Jin, Xinchun; McClure-Begley, Tristan D et al. (2018) Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of ?4?2* nAChRs in Wistar male rats. Pharmacol Biochem Behav 171:54-65
Moretti, Milena; Fasoli, Francesca; Gotti, Cecilia et al. (2018) Reduced ?4 subunit expression in ?4+- and ?4+- /?2+- nicotinic acetylcholine receptors alters ?4?2 subtype up-regulation following chronic nicotine treatment. Br J Pharmacol 175:1944-1956
Locker, Alicia R; Marks, Michael J; Kamens, Helen M et al. (2016) Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice. Brain Res Bull 123:13-22
McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L et al. (2016) Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex. eNeuro 3:
Pistillo, Francesco; Fasoli, Francesca; Moretti, Milena et al. (2016) Chronic nicotine and withdrawal affect glutamatergic but not nicotinic receptor expression in the mesocorticolimbic pathway in a region-specific manner. Pharmacol Res 103:167-76
Fasoli, F; Moretti, M; Zoli, M et al. (2016) In vivo chronic nicotine exposure differentially and reversibly affects upregulation and stoichiometry of ?4?2 nicotinic receptors in cortex and thalamus. Neuropharmacology 108:324-31
Marks, Michael J; O'Neill, Heidi C; Wynalda-Camozzi, Kelly M et al. (2015) Chronic treatment with varenicline changes expression of four nAChR binding sites in mice. Neuropharmacology 99:142-55
Sanjakdar, Sarah S; Maldoon, Pretal P; Marks, Michael J et al. (2015) Differential roles of ?6?2* and ?4?2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. Neuropsychopharmacology 40:350-60
Meyers, Erin E; Loetz, Esteban C; Marks, Michael J (2015) Differential expression of the beta4 neuronal nicotinic receptor subunit affects tolerance development and nicotinic binding sites following chronic nicotine treatment. Pharmacol Biochem Behav 130:1-8
Carroll, F Ivy; Navarro, Hernán A; Mascarella, S Wayne et al. (2015) In vitro and in vivo neuronal nicotinic receptor properties of (+)- and (-)-pyrido[3,4]homotropane [(+)- and (-)-PHT]: (+)-PHT is a potent and selective full agonist at ?6?2 containing neuronal nicotinic acetylcholine receptors. ACS Chem Neurosci 6:920-6

Showing the most recent 10 out of 140 publications