Among drug dependence disorders, nicotine dependence is the most widely diffused, with a strong impact on the world's health and economy. The tobacco epidemic is a global problem;one-third of the worldwide population over 15 years of age or 1.1 billion people smoke. By the year 2025, the WHO estimates there will be 10 million tobaccorelated deaths per year worldwide. Smoking cessation treatment is highly cost-effective, and pharmacotherapy is universally recommended for treatment of nicotine dependence in the absence of specific contraindications. However, the majority of smokers do not quit even with treatment. Currently available treatments do not exploit recent advances inknowledge of neurobiologic mechanisms of addiction and reward that have made possible the development of rationally designed treatments targeting specifically those systems involved in nicotine reward circuitry. Existing and new pharmacotherapies along with prevention efforts are key to improving smoking cessation rates and reducing the premature and preventable morbidity and mortality associated with tobacco use. This RFA has prompted three organizations with longstanding interest in pharmacotherapy for nicotine dependence, Massachusetts General Hospital (MGH), McLean Hospital Brain Imaging Center (BIC), and GlaxoSmithKline (GSK), to join forces for the proposed NCDDG-MD/NA Group. The primary objective of this group is to identify and test promising compounds that affect critical neural systems in nicotine reward and craving. In this collaborative group project for drug discovery, we will combine screening of multiple potential lead compounds, with pre-clinical and clinical testing of two compounds and in vivo brain imaging measures. Specifically, we will 1) screen multiple lead compounds in neurochemistry, electrophysiology, behavioral and animal brain imaging assays, 2) screen multiple promising compounds identified in the preclinical work in a novel human 72 hour nicotine craving paradigm, 3) perform clinical trials to test the efficacy of the most promising two compounds for smoking cessation, compared with placebo and bupropion and 4) use in vivo neuroimaging to identify surrogate markers for treatment response and relapse in humans. This effort will advance our understanding of mechanisms involved in nicotine dependence, early abstinence/treatment response and relapse, will advance our understanding of what types of agents are effective in treating nicotine dependence, will test a battery of putative surrogate markers for clinical response aimed at accelerating the process by which effective drugs can be assessed for efficacy in nicotine dependence and will test two compounds for nicotine dependence in adequately powered trials. The compounds that we will investigate will be drawn from the large, existing portfolio of compounds under development for nicotine dependence at GSK. Each organization will make a unique contribution of personnel and resources to the implementation and success of the project.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DA019378-05S2
Application #
8116261
Study Section
Special Emphasis Panel (ZMH1-BRB-S (09))
Program Officer
Biswas, Jamie
Project Start
2004-09-30
Project End
2013-02-28
Budget Start
2010-09-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$549,947
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
(2017) Erratum to: ""Ventral and Dorsal Striatum Networks in Obesity: Link to Food Craving and Weight Gain"" by Contreras-Rodriguez et al. (Biol Psychiatry 2017; 81:789-796). Biol Psychiatry 81:1050
Janes, Amy C; Pedrelli, Paola; Whitton, Alexis E et al. (2015) Reward Responsiveness Varies by Smoking Status in Women with a History of Major Depressive Disorder. Neuropsychopharmacology 40:1940-6
Janes, Amy C; Nickerson, Lisa D; Frederick, Blaise De B et al. (2012) Prefrontal and limbic resting state brain network functional connectivity differs between nicotine-dependent smokers and non-smoking controls. Drug Alcohol Depend 125:252-9
Janes, Amy C; Smoller, Jordan W; David, Sean P et al. (2012) Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women. Drug Alcohol Depend 120:7-13
Evins, A Eden; Pachas, Gladys; Mischoulon, David et al. (2011) A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females. J Clin Psychopharmacol 31:597-602
Mashhoon, Yasmin; Janes, Amy C; Jensen, J Eric et al. (2011) Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome. Prog Neuropsychopharmacol Biol Psychiatry 35:1709-13
Janes, Amy C; Pizzagalli, Diego A; Richardt, Sarah et al. (2010) Neural substrates of attentional bias for smoking-related cues: an FMRI study. Neuropsychopharmacology 35:2339-45
Janes, Amy C; Pizzagalli, Diego A; Richardt, Sarah et al. (2010) Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry 67:722-9
Kaufman, Marc J; Prescot, Andrew P; Ongur, Dost et al. (2009) Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study. Psychiatry Res 173:143-9
Janes, Amy C; Frederick, Blaise deB; Richardt, Sarah et al. (2009) Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence. Exp Clin Psychopharmacol 17:365-73