The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats

Rationale: Intermittent footshock stress reliably reinstates extinguished a lcohol-taking behavior in drug-free rats, but the neurochemical events invo lved in this effect are not known. Objective: We studied here whether two m ain modulators of stress responses, corticotropin-releasing factor (CRF) an d corticosterone, are involved in reinstatement of alcohol seeking induced by the intermittent footshock stressor. Methods: Rats were given alcohol in a two-bottle choice procedure (water versus alcohol) for 30 days and were then trained for 60 min per day to press a lever for alcohol (12% w/v) for 24-30 days in operant conditioning chambers. After stable drug-taking behav ior was obtained, lever pressing for alcohol was extinguished by terminatin g drug delivery for 5-8 days. Reinstatement of alcohol seeking was then det ermined after exposure to intermittent footshock (0.8 mA; 10 min) in differ ent groups of rats that were pretreated with CRF receptor antagonists or un derwent adrenalectomy (ADX) to remove endogenous corticosterone from the bo dy. Results: The CRF receptor antagonists, d-phe-CRF (0.3 or 1.0 mu g; ICV) and CP-154,526 (15, 30 or 45 mg/kg; IP) attenuated footshock-induced reins tatement of alcohol seeking in a dose dependent manner. In contrast, the re moval of circulating corticosterone by ADX had no effect on footshock stres s-induced reinstatement of alcohol-taking behavior. In addition, the preven tion of the footshock-induced rise In corticosterone while maintaining basa l levels of the hormone by providing adrenalectomized rats with corticoster one pellets (50 mg/kg per day), had no effect on stress-induced reinstateme nt. Conclusions: These data suggest that CRF contributes to stress-induced relapse to alcohol seeking via its actions on extra-hypothalamic sites. The present data, and previous data with heroin- and cocaine-trained rats, poi nt to a general role of CRF in relapse to drugs induced by stressors.