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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013108-06
Application #
7392416
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2001-04-01
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
6
Fiscal Year
2008
Total Cost
$145,800
Indirect Cost
Name
Centre for Addiction and Mental Health
Department
Type
DUNS #
207855271
City
Toronto
State
ON
Country
Canada
Zip Code
M5S2S-1
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
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
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
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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