High rates of relapse to alcohol are a major clinical problem. An important factor for provoking relapse to alcohol in humans is exposure to stress. However, until recently a preclinical model to study this phenomenon under controlled experimental conditions did not exist. We have developed a reinstatement procedure to study the effect of exposure to stress on relapse to alcohol seeking in alcohol-experienced rats that are drug-free at the time of testing. Using this model, we previously found that exposure to intermittent footshock stress reinstates alcohol seeking, providing the first preclinical demonstration of stress-induced relapse to alcohol seeking. During the initial grant period, we identified key roles for brain serotonin (5-hydroxytryptamine, 5-HT), corticotropin-releasing factor (CRF), and noradrenaline (NA) in stress-induced relapse to alcohol seeking. We also found that the alpha-2 adrenoceptor antagonist yohimbine, which induces stress-and anxiety-like responses in recovering alcoholics, not only potently reinstated alcohol seeking in drug-free rats, but also induced more than two-fold increases in alcohol self-administration. These data provide the first demonstration of a stress manipulation that profoundly enhances alcohol-taking behavior in two critical phases of the alcohol addiction process: maintenance and relapse. In the present competitive renewal, we propose to characterize the neurochemical bases of yohimbineinduced alcohol-taking behavior. We hope that data from our preclinical model will lead to the development of medications for the treatment of alcohol addiction.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grakalic, Ivana
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Centre for Addiction and Mental Health
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Funk, D; Lo, S; Coen, K et al. (2016) Effects of varenicline on operant self-administration of alcohol and/or nicotine in a rat model of co-abuse. Behav Brain Res 296:157-162
Li, Sophia; Zou, Sheng; Coen, Kathleen et al. (2014) Sex differences in yohimbine-induced increases in the reinforcing efficacy of nicotine in adolescent rats. Addict Biol 19:156-64
Lê, A D; Funk, Douglas; Lo, Steven et al. (2014) Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse. Psychopharmacology (Berl) 231:4019-29
Zou, Sheng; Funk, Douglas; Shram, Megan J et al. (2014) Effects of stressors on the reinforcing efficacy of nicotine in adolescent and adult rats. Psychopharmacology (Berl) 231:1601-14
Grella, Stephanie L; Funk, Douglas; Coen, Kathy et al. (2014) Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats. Behav Brain Res 265:188-97
Funk, Douglas; Coen, Kathleen; Lê, A D (2014) The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats. Brain Behav 4:356-67
Le, A D; Funk, Douglas; Coen, Kathleen et al. (2013) Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats. Addict Biol 18:448-51
Lê, A D; Funk, Douglas; Juzytsch, Walter et al. (2011) Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology (Berl) 218:89-99
Le, A D; Lo, Steven; Harding, Stephen et al. (2010) Coadministration of intravenous nicotine and oral alcohol in rats. Psychopharmacology (Berl) 208:475-86
Marinelli, Peter W; Funk, Douglas; Juzytsch, Walter et al. (2010) Opioid receptors in the basolateral amygdala but not dorsal hippocampus mediate context-induced alcohol seeking. Behav Brain Res 211:58-63

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