Sensitivity to intravenous nicotine in smokers: genetic moderators Abstract: Smoking is an important public health problem costing over 430,000 lives a year in the U.S. alone. The biological mechanisms contributing to nicotine reward have not been well elucidated in humans. Increasing evidence suggests that mu opioid receptors (MOR) likely contribute to the rewarding effect of nicotine as well as sex differences in nicotine reward. Further, a functional polymorphism in the MOR gene (OPRM1), A118G (Asn40Asp), has been associated with rewarding effects of alcohol in alcohol users and nicotine in female smokers. The proposed study will extend these previous findings by evaluating the OPRM1 A118G polymorphism in male and female smokers as a moderator of the subjective-rewarding effects of intravenous (IV) nicotine. The IV nicotine administration procedure that we have developed shows promise for evaluation of genetic moderators of nicotine sensitivity in both male and female smokers. As an exploratory aim, we will also evaluate the influence of rs16969968 SNP at the 15 nicotinic cholinergic receptor gene (CHRNA5). Since, variation at this SNP, G398A, seems to enhance responses to nicotinic agonist in vitro, it is of interest to evaluate its effects on nicotine responses in humans. The proposed study is expected to fill a critical gap in our understanding of genetic factors moderating dose-dependent rewarding effects of nicotine. By providing a better understanding of biological mechanisms of nicotine reward, this study may contribute to development of more effective treatments for smoking cessation.

Public Health Relevance

Smoking is an important public health problem costing over 430,000 lives a year in the U.S. alone. This proposed study will seek to determine the genetic factor moderating nicotine's rewarding effects. By providing a better understanding of biological mechanisms of nicotine reward, this study may contribute to development of more effective treatments for smoking cessation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA027474-02
Application #
7934647
Study Section
Special Emphasis Panel (ZDA1-SXC-E (03))
Program Officer
Kautz, Mary A
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$190,983
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Jensen, K P; Smith, A H; Herman, A I et al. (2017) A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke. Mol Psychiatry 22:242-249
Jensen, Kevin P; DeVito, Elise E; Herman, Aryeh I et al. (2015) A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. Neuropsychopharmacology 40:2813-21
Jensen, K P; Herman, A I; Morean, M E et al. (2015) FKBP5 variation is associated with the acute and chronic effects of nicotine. Pharmacogenomics J 15:340-6
Herman, Aryeh I; DeVito, Elise E; Jensen, Kevin P et al. (2014) Pharmacogenetics of nicotine addiction: role of dopamine. Pharmacogenomics 15:221-34
DeVito, Elise E; Herman, Aryeh I; Waters, Andrew J et al. (2014) Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacology 39:1431-40
Herman, A I; Jatlow, P I; Gelernter, J et al. (2013) COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. Pharmacogenomics J 13:490-7
Sofuoglu, Mehmet; Herman, Aryeh I; Nadim, Haleh et al. (2012) Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 37:1509-16