Recent analyses of several human populations have identified a number of genetic markers which correlate with aspects of smoking behavior and that correspond to different nAChR subunits. These studies strongly support the contention that genetic differences in receptor subunit structure or expression influence tobacco use. However, it has not been established which of the genetic differences encourage and which discourage tobacco use. Chronic exposure of animals to nicotine, or of humans to tobacco, results in the development of tolerance and dependence. The initial sites of action of nicotine are the nicotinic cholinergic receptors (nAChR), for which the native neurotransmitter is acetylcholine. There are many different types of nAChR in the brain and in the periphery. Nicotine's interaction with these various receptors differs and can lead to different responses to the drug. It is well established that chronic nicotine exposure also changes the number, and perhaps the function, of some nicotinic cholinergic receptors (nAChR). However, chronic nicotine exposure does not affect each nAChR subtype in the same way. Mice will be used as the model organism to examine effects of chronic nicotine treatment. The effects of nicotine in mice are influenced by genotype and mice from which a specific nAChR gene has been deleted (knockout) or mutated (knockin) have been generated. The knockout and knockin mice will be used to investigate some behavioral changes induced by nicotine treatment, primarily tolerance. Furthermore, the effects of chronic nicotine treatment on the expression and function of several different nAChR subtypes will be measured. There are two specific aims. The role of ?4?2*nAChR in modulating response to chronic nicotine will be investigated in Aim 1. ?4?2*- nAChR is the most highly expressed subtype in the brain and chronic nicotine treatment increases the number of these receptors. We plan four types of experiments to study this response in detail a) measure effects in ?4 knockouts, where the gene is completely gone;b) measure the response in mice in which either or both ?4 and ?2 genes have been partially deleted;c) measure response in mice expressing mutations that make these receptors hypersensitive;and d) evaluate the effects of treatment with a drug that interacts selectively with ?4?2-nAChR. The role of the ?5 and ?4 subunits in modulating responses to chronic nicotine will be investigated in Aim 2. ?5 is interesting because it is the nAChR gene that most robustly correlates with tobacco use, while ?4 is interesting because nAChR incorporating this subunit affect nicotine withdrawal and may diminish tolerance development. Response of ?5 and ?4 null mutant and heterozygote mice will be compared to that of wild-type mice. The results of these studies will provide new information on the regulation of the major nicotinic receptor subtype and the contribution of two other subtypes to changes induced by chronic nicotine. The results could also help identify specific behavioral and biochemical responses to chronic nicotine mediated by genes identified as important factors in human smoking.

Public Health Relevance

Chronic use of nicotine or tobacco changes the amount of the specific nicotine-binding molecules (receptors) in both humans and laboratory animals. We will study the responses that chronic nicotine treatment elicits in mice that express fewer or different receptors to determine how these molecular differences affect aspects of nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003194-30
Application #
8261962
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pollock, Jonathan D
Project Start
1983-09-30
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
30
Fiscal Year
2012
Total Cost
$491,222
Indirect Cost
$149,879
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
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:
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
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
Sanjakdar, Sarah S; Maldoon, Pretal P; Marks, Michael J et al. (2015) Differential roles of α6β2* and α4β2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. Neuropsychopharmacology 40:350-60
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 α6β2 containing neuronal nicotinic acetylcholine receptors. ACS Chem Neurosci 6:920-6
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
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
McClure-Begley, Tristan D; Grady, Sharon R; Marks, Michael J et al. (2014) Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. Biochem Pharmacol 91:87-96
Wageman, Charles R; Marks, Michael J; Grady, Sharon R (2014) Effectiveness of nicotinic agonists as desensitizers at presynaptic *4*2- and *4*5*2-nicotinic acetylcholine receptors. Nicotine Tob Res 16:297-305
Sala, Mariaelvina; Braida, Daniela; Pucci, Luca et al. (2013) CC4, a dimer of cytisine, is a selective partial agonist at ýý4ýý2/ýý6ýý2 nAChR with improved selectivity for tobacco smoking cessation. Br J Pharmacol 168:835-49

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