This is a revision of a new application in response to PA-00-045 Neurobiological and Behavioral Research on Nicotine and Tobacco Components. Nicotine activates a4beta2 nicotinic receptors on mesolimbic dopamine neurons and increases extra cellular dopamine release. The indirect dopamine agonist effects of both nicotine and cocaine are thought to be important for their abuse-related effects. However, it is likely that dopamine is only one of a constellation of neurobiological systems that may contribute to nicotine abuse as well as to cocaine abuse. The role of the endocrine system in modulating the reinforcing effects of drugs is poorly understood, but recent preclinical and clinical studies suggest that hormones may influence the abuse-related effects of cocaine, and these findings have led to novel approaches to treatment. Our preliminary studies indicate that both nicotine and cocaine stimulate anterior pituitary and adrenal hormones, and have similar pharmacodynamic and pharmacokinetic profiles. However, in contrast to cocaine, relatively little is known about the temporal relationships between nicotine-induced alterations in subjective states, hormone release patterns and increases in plasma nicotine levels, or how nicotine's effects may vary as a function of gender and/or menstrual cycle phase. We propose to conduct clinical studies of the acute effects of nicotine on the hypothalamic-pituitary-adrenal axis (HPA) and the hypothalamic-pituitary-gonadal axis (HPG) in men and women who are daily smokers and are nicotine dependent (DSM-IV criteria). Women will be studied at the follicular and the mid-luteal phases of the menstrual cycle to determine if hormone fluctuations across the menstrual cycle influence nicotine's biological and abuse-related effects. The effects of two doses of nicotine and placebo on neuroendocrine, subjective and cardiovascular measures will be studied under double-blind conditions in an own control design. Nicotine will be administered by smoking in a procedure where puff volume, duration and frequency are measured and controlled. However, because other constituents of tobacco smoke may contribute to the effects of smoking, we propose to conduct parallel studies of intravenous nicotine. Examination of nicotine's effects on the endocrine system and correlated changes in subjective and cardiovascular measures will advance our understanding of the biological bases of nicotine's abuse-related effects, as well as its contribution to some reproductive disorders in women who smoke (e.g., early menopause and infertility). Clinical reports suggest that nicotine has anti-estrogenic effects, but there have been no comprehensive studies of nicotine's effects on the HPG axis. This question is important, because gonadal steroid hormones appear to enhance the abuse-related effects of cocaine in preclinical studies and may contribute to gender differences in cocaine's effects. We propose to study the temporal relations between nicotine's effects on gonadal steroid hormones, subjective effects and cardiovascular measures. An increased understanding of nicotine's acute effects on anterior pituitary, gonadal and adrenal hormones may suggest new strategies for the development of antinicotine medications as it has for cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015067-03
Application #
6849777
Study Section
Biobehavioral and Behavioral Processes 3 (BBBP)
Program Officer
Hoffman, Allison
Project Start
2003-03-20
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$316,000
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Goletiani, Nathalie V; Siegel, Arthur J; Lukas, Scott E et al. (2015) The effects of smoked nicotine on measures of subjective states and hypothalamic-pituitary-adrenal axis hormones in women during the follicular and luteal phases of the menstrual cycle. J Addict Med 9:195-203
Mello, Nancy K; Peltier, Mackenzie R; Duncanson, Haley (2013) Nicotine levels after IV nicotine and cigarette smoking in men. Exp Clin Psychopharmacol 21:188-95
Mello, Nancy K (2010) Hormones, nicotine, and cocaine: clinical studies. Horm Behav 58:57-71
Mendelson, Jack H; Goletiani, Nathalie; Sholar, Michelle B et al. (2008) Effects of smoking successive low- and high-nicotine cigarettes on hypothalamic-pituitary-adrenal axis hormones and mood in men. Neuropsychopharmacology 33:749-60
Goletiani, Nathalie V; Keith, Diana R; Gorsky, Sara J (2007) Progesterone: review of safety for clinical studies. Exp Clin Psychopharmacol 15:427-44
Mendelson, Jack H; Sholar, Michelle B; Goletiani, Nathalie et al. (2005) Effects of low- and high-nicotine cigarette smoking on mood states and the HPA axis in men. Neuropsychopharmacology 30:1751-63
Mendelson, Jack H; Sholar, Michelle B; Mutschler, Nicole H et al. (2003) Effects of intravenous cocaine and cigarette smoking on luteinizing hormone, testosterone, and prolactin in men. J Pharmacol Exp Ther 307:339-48