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.
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