Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. Adults currently smoking (CDC, 2007). Though there are medications approved by the FDA to treat nicotine addiction, a clinical study evaluating two of these drugs, varenicline and bupropion, showed that at least 80% of the treatment group participants relapsed within one year (Gonzales, et al., 2006). Interestingly, failed smoking cessation has been shown to have genetic contributions (Xian et al., 2003~ Broms et al., 2006~ Lessov et al., 2004). Though development of novel compounds may yield more promising drugs, a new strategy tailoring pharmacotherapies to genetic information is the next frontier in the treatment of nicotine addiction (Ho et al., 2010). However, though there are genome-wide association studies demonstrating a genetic contribution in nicotine addiction, there are no published studies addressing th mechanism of pharmacogenetics in treating nicotine dependence. One protein associated with mechanisms of both gene regulation and nicotine response is the transcription factor CREB. Experiments outlined in this proposal aim to investigate the role of CREB and associated genomic mechanisms in the potential therapeutic application of two nicotinic compounds for treatment of nicotine addiction, and elucidate possible mechanisms of action using cutting-edge molecular, functional, and behavioral techniques. My research so far in the nicotinic field has given me a solid foundation in basic science approaches, including biochemistry, pharmacology, and animal behavior. However, the specialized training proposed in genomics and functional imaging during the K99 phase of this award will broaden my knowledge base and increase the translational impact of my research. Furthermore, this training and individualized research project will serve me well during job searches for an academic tenure-track position.

Public Health Relevance

Nicotine is the most highly addictive and highly abused drug in the world. Although there are a number of pharmacotherapies for smoking cessation, quitting success rate remains less than 20%. The proposed research will be directed towards a pharmacogenetic understanding of nicotine dependence, using state of the art genomic and functional techniques. This project will not only help us better understand why current treatment success rates are so low, but it will identify new pharmacological targets for smoking cessation and perhaps indicate how tailoring these drugs to an individual's genetics can improve quit rates. .

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Career Transition Award (K99)
Project #
1K99DA032681-01A1
Application #
8443070
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sorensen, Roger
Project Start
2013-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$133,182
Indirect Cost
$9,865
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Forcelli, Patrick A; Turner, Jill R; Lee, Bridgin G et al. (2016) Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101:46-56
Mague, Stephen D; Port, Russell G; McMullen, Michael E et al. (2015) Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function. Neuropharmacology 97:426-35
Hussmann, G Patrick; DeDominicis, Kristen E; Turner, Jill R et al. (2014) Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain. J Neurochem 129:721-31
Afshordel, Sarah; Wood, Wellington Gibson; Igbavboa, Urule et al. (2014) Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain. J Neurochem 129:732-42
Turner, J R; Ray, R; Lee, B et al. (2014) Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 19:801-10
Yohn, Nicole L; Turner, Jill R; Blendy, Julie A (2014) Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors. J Pharmacol Exp Ther 349:348-54
Turner, Jill R; Wilkinson, Derek S; Poole, Rachel Lf et al. (2013) Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal. Neuropsychopharmacology 38:2035-47
Turner, Jill R; Ecke, Laurel E; Briand, Lisa A et al. (2013) Cocaine-related behaviors in mice with deficient gliotransmission. Psychopharmacology (Berl) 226:167-76
Wilkinson, Derek S; Turner, Jill R; Blendy, Julie A et al. (2013) Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology (Berl) 225:201-8
Ortinski, Pavel I; Turner, Jill R; Pierce, R Christopher (2013) Extrasynaptic targeting of NMDA receptors following D1 dopamine receptor activation and cocaine self-administration. J Neurosci 33:9451-61

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