Tobacco use is a chronic relapsing disorder. Recurrent resumption of tobacco use after abstinence is one of the principal characteristics of nicotine addiction. Only approximately 3% of smokers successfully remain abstinent each year. The very high vulnerability to relapse following abstinence presents a formidable challenge for the treatment of nicotine addiction. One explanation for the persistence of addictive behavior and high risk of relapse after abstinence is the conditioning hypothesis, which is based on the observations that relapse is often associated with exposure to drug-related environmental stimuli. Over time, and after thousands of such pairings, the smoking-related stimuli (e.g., finishing a meal, the consumption of alcoholic beverages, being with friends who smoke, drinking coffee, reading the morning newspaper) become cues that elicit subjective states that can trigger craving, drug-seeking behavior and the resumption of nicotine use. The pervasive nature of these nicotine-associated cues in daily life suggests that cues might play a bigger role in nicotine addiction compared to other drugs of abuse. Although human studies have shown that environmental stimuli associated with nicotine use produce physiological and subjective changes in abstinent smokers, the significance of nicotine-related cues in triggering relapse has received little experimental attention. The proposed experiments are designed using an animal model of relapse to investigate the environmental and neuropharmacological bases of nicotine-seeking behavior associated with exposure to drug cues. The animal model will employ a response-reinstatement procedure where animals are initially trained to self-administer nicotine by pressing a lever in operant conditioning chambers and then the drug-reinforced behavior is extinguished by withholding the drug delivery. After extinction of the nicotine-reinforced behavior, the ability of nicotine-related stimuli (i.e., cues), nicotine itself (i.e., priming), and both to reinstate nicotine-seeking is determined. There has been an increasing use of these reinstatement procedures in recent years, and they have provided very important information on the neurobiological bases of drug (mainly cocaine and alcohol) use and relapse. The proposed experiments will characterize the motivational significance of nicotine-associated cues, nicotine priming, and their combination in an operant response-reinstatement model of relapse and determine whether the response-reinstating effects of nicotine cues, nicotine priming and their combination are sensitive to pharmacological antagonism of dopaminergic and nicotinic neurotransmission. The results of the proposed studies will provide important basic information on the role of nicotine-associated cues in the re-initiation of nicotine-seeking behavior. Results will not only lay the groundwork for future preclinical studies, but also will be useful in designing future trials to prevent relapse in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017288-04
Application #
7388306
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Lynch, Minda
Project Start
2005-05-01
Project End
2008-08-31
Budget Start
2008-04-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$165,661
Indirect Cost
Name
University of Pittsburgh
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Liu, Xiu (2015) Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity. Psychopharmacology (Berl) 232:2049-60
Liu, Xiu (2014) Effects of blockade of ?4?2 and ?7 nicotinic acetylcholine receptors on cue-induced reinstatement of nicotine-seeking behaviour in rats. Int J Neuropsychopharmacol 17:105-16
Liu, Xiu (2013) Positive allosteric modulation of ?4?2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration. Psychopharmacology (Berl) 230:203-13
Liu, Xiu; Jernigan, Courtney (2012) Effects of caffeine on persistence and reinstatement of nicotine-seeking behavior in rats: interaction with nicotine-associated cues. Psychopharmacology (Berl) 220:541-50
Liu, Xiu; Jernigan, Courtney (2011) Activation of the opioid ýý1, but not ýý or ýý, receptors is required for nicotine reinforcement in a rat model of drug self-administration. Prog Neuropsychopharmacol Biol Psychiatry 35:146-53
Liu, Xiu; Jernigen, Courtney; Gharib, Maysa et al. (2010) Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats. Behav Pharmacol 21:153-60
Caggiula, Anthony R; Donny, Eric C; Palmatier, Matthew I et al. (2009) The role of nicotine in smoking: a dual-reinforcement model. Nebr Symp Motiv 55:91-109
Liu, Xiu; Palmatier, Matthew I; Caggiula, Anthony R et al. (2009) Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats. Psychopharmacology (Berl) 202:589-98
Palmatier, M I; Coddington, S B; Liu, X et al. (2008) The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose. Neuropharmacology 55:1425-30
Liu, Xiu; Caggiula, Anthony R; Palmatier, Matthew I et al. (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology (Berl) 196:365-75

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