Despite evidence of strong genetic contributions to the etiology of smoking initiation (SI) and nicotine dependence (ND), we are far from identifying the specific genetic basis of individual susceptibility to ND. This project - to deepen our understanding of how genes contribute to risk for nicotine dependence (ND) - has arisen as an effort to utilize maximally the relatively unique and complementary set of skill of this group of investigators in complex human genetics, animal genetics and nicotine pharmacology. We will validate these putative risk genes using a two-step approach: replication in other human samples and the demonstration in animal models of ND that variants in these genes contribute to neurobiological pathways likely involved in ND. We will first identify promising candidate genes for smoking initiation (SI) and ND by data-mining GWA datasets and the selected candidates will be replicated. Using a mouse model of nicotine withdrawal, we will characterize behavioral QTLs relevant for ND using a recently developed expanded BXD RI mouse strain panel, focusing on strains informative for already identified areas of provisional QTLs. This approach allows us to both validate and refine our mapping of the nicotine behavioral QTL. Furthermore, we will identify candidate genes for ND by combining expression and behavioral genetics analyses in these BXD RI mouse strains. Candidate genes/pathways identified and prioritized from human and mouse studies will be validated by pharmacological or genetic manipulations to alter expression or function of candidate genes in mouse brain and determine effects on behavioral responses to in models of nicotine reward and withdrawal.

Public Health Relevance

Tobacco smoking results in millions of deaths worldwide each year even when using the most efficacious smoking cessation agents available. Indeed, approximately 75 to 80% of smokers attempting to quit will relapse within one year, highlighting the need to develop more effective smoking cessation agents. Here, using human and animal models we will deepen our understanding of how genes contribute to risk for nicotine dependence. If successful, this application promises to have a significant positive impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA032246-05
Application #
9220796
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02)M)
Program Officer
Lossie, Amy N
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
5
Fiscal Year
2017
Total Cost
$274,500
Indirect Cost
$94,500
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Kota, Dena; Alajaji, Mai; Bagdas, Deniz et al. (2018) Early adolescent nicotine exposure affects later-life hippocampal mu-opioid receptors activity and morphine reward but not physical dependence in male mice. Pharmacol Biochem Behav 173:58-64
Bagdas, Deniz; Alkhlaif, Yasmin; Jackson, Asti et al. (2018) New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice. Neuropharmacology 138:72-79
Jackson, Asti; Papke, Roger L; Damaj, M Imad (2018) Pharmacological modulation of the ?7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psychopharmacology (Berl) 235:1897-1905
Jackson, Asti; Bagdas, Deniz; Muldoon, Pretal P et al. (2017) In vivo interactions between ?7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-?: Implication for nicotine dependence. Neuropharmacology 118:38-45
Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj et al. (2016) Functional interaction between Lypd6 and nicotinic acetylcholine receptors. J Neurochem 138:806-20
Slater, Cassandra A; Jackson, Asti; Muldoon, Pretal P et al. (2016) Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse. Alcohol Clin Exp Res 40:62-72
Bowers, M S; Jackson, A; Maldoon, P P et al. (2016) N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice. Psychopharmacology (Berl) 233:995-1003
Alajaji, Mai; Lazenka, Matthew F; Kota, Dena et al. (2016) Early adolescent nicotine exposure affects later-life cocaine reward in mice. Neuropharmacology 105:308-317
Ware, Jennifer J; Chen, Xiangning; Vink, Jacqueline et al. (2016) Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2. Sci Rep 6:20092
Chen, Jingchun; Bacanu, Silviu-Alin; Yu, Hui et al. (2016) Genetic Relationship between Schizophrenia and Nicotine Dependence. Sci Rep 6:25671

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