Consistent with the aims of the IRCSSA, this R01 application will examine whether noradrenergic agents,shown to be effective in improving stress-induced decrements in self-control (see Project 2: PI - Arnsten) andto attenuate stress-induced reinstatement to drug use with pre-clinical models, will attenuate the ability ofstress to precipitate smoking lapse behavior in humans. Several lines of evidence identify that stress is aprimary mechanism involved in smoking relapse. Despite this knowledge, targeting stress-related relapse asa viable medications development strategy for nicotine dependence has not yet been explored. For thecurrent proposal, we are planning to continue with the development of a novel self-administration paradigmto examine how stress facilitates lapse behavior for the purpose of medication screening. The firstoccurrence of smoking during a cessation attempt is a critical transition, and represents an important targetfor medication development. Our lapse model is focused on two primary aspects of early lapse behavior: 1)ability to resist the first cigarette, representing a laboratory marker of self-control and 2) subsequentsmoking. We have several ongoing studies utilizing this smoking-lapse model to examine variousprecipitants of relapse (stress, nicotine deprivation, food deprivation, alcohol, cigarette availability) and arecurrently using these models to examine effects of medications hypothesized to influence the models' primes(R21DA017234; P50AA015632; P50DA013334). Use of such laboratory-based paradigms provides a meansto efficiently and cost-effectively screen new therapeutics, and to translate pre-clinical findings generated byIRCSSA Projects 2 to 5, to relapse behavior in humans.The primary aim of STUDY 1 will be to finalize the parameters of the Stress-Lapse Model, which willmodel the effect of stress + nicotine deprivation + cigarette availability on the inability to resist smoking indaily smokers. Secondarily, we will examine potential mechanisms underlying stress-precipitated smokinglapse behavior including self-control, craving, mood, cardiovascular reactivity, stress-related neuroendocrinemeasures, neuropeptides, and endocannabinoids. For STUDY 2 (Guanfacine, an alpha-2 adrenergicreceptor agonist) and STUDY 3 (Carvedilol, an alpha-1 and beta adrenergic blocker), we will use the Stress-Lapse Model to examine whether noradrenergic agents attenuate the ability of stress to precipitate smokinglapse behavior, and will explore potential mechanisms for medication effects. Results will provide importantevidence that targeting stress-related relapse is a viable medications development strategy for nicotinedependence, and will provide the impetus to expand this investigation to other addictive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Linked Research project Grant (RL1)
Project #
1RL1DA024857-01
Application #
7466492
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Hoffman, Allison
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2007-09-30
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$247,500
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Verplaetse, Terril L; Weinberger, Andrea H; Ashare, Rebecca L et al. (2018) Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior. J Psychopharmacol 32:1003-1009
Verplaetse, Terril L; Smith, Philip H; Smith, Kathryn M Z et al. (2017) Guanfacine alters the effect of stress and smoking on heart rate variability in regular daily smokers. Psychopharmacology (Berl) 234:805-813
Weinberger, Andrea H; Pittman, Brian; Mazure, Carolyn M et al. (2015) A behavioral smoking treatment based on perceived risks of quitting: A preliminary feasibility and acceptability study with female smokers. Addict Res Theory 23:108-114
McKee, Sherry A; Potenza, Marc N; Kober, Hedy et al. (2015) A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol 29:300-11
Udo, Tomoko; Weinberger, Andrea H; Grilo, Carlos M et al. (2014) Heightened vagal activity during high-calorie food presentation in obese compared with non-obese individuals--results of a pilot study. Obes Res Clin Pract 8:e201-98
Weinberger, Andrea H; Pilver, Corey E; Desai, Rani A et al. (2013) The relationship of dysthymia, minor depression, and gender to changes in smoking for current and former smokers: longitudinal evaluation in the U.S. population. Drug Alcohol Depend 127:170-6
Udo, Tomoko; Grilo, Carlos M; Brownell, Kelly D et al. (2013) Modeling the effects of positive and negative mood on the ability to resist eating in obese and non-obese individuals. Eat Behav 14:40-6
McKee, Sherry A; Weinberger, Andrea H (2013) How can we use our knowledge of alcohol-tobacco interactions to reduce alcohol use? Annu Rev Clin Psychol 9:649-74
Weinberger, Andrea H; Pilver, Corey E; Hoff, Rani A et al. (2013) Changes in smoking for adults with and without alcohol and drug use disorders: longitudinal evaluation in the US population. Am J Drug Alcohol Abuse 39:186-93
Weinberger, Andrea H; McKee, Sherry A (2012) Mood and smoking behavior: the role of expectancy accessibility and gender. Addict Behav 37:1349-52

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