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.
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