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.
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.
|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|
|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|
|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|
|Bagdas, Deniz; Wilkerson, Jenny L; Kulkarni, Abhijit et al. (2016) The Î±7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. Br J Pharmacol 173:2506-20|
|Chen, Jingchun; Bacanu, Silviu-Alin; Yu, Hui et al. (2016) Genetic Relationship between Schizophrenia and Nicotine Dependence. Sci Rep 6:25671|
|Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj et al. (2016) Functional interaction between Lypd6 and nicotinic acetylcholine receptors. J Neurochem 138:806-20|
|Bagdas, Deniz; AlSharari, Shakir D; Freitas, Kelen et al. (2015) The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain. Biochem Pharmacol 97:590-600|
|Jackson, Kia J; Jackson, Asti; Carroll, F Ivy et al. (2015) Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice. Neuropharmacology 97:270-4|
|Sanjakdar, Sarah S; Maldoon, Pretal P; Marks, Michael J et al. (2015) Differential roles of Î±6Î²2* and Î±4Î²2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. Neuropsychopharmacology 40:350-60|
|Papke, Roger L; Bagdas, Deniz; Kulkarni, Abhijit R et al. (2015) The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 91:34-42|
Showing the most recent 10 out of 15 publications