The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats.
BACKGROUND
Intermittent footshock stress reliably reinstates extinguished alcohol-taking behavior in drug-free rats, but the neurochemical events involved in this effect are not known.


OBJECTIVE
We studied here whether two main modulators of stress responses, corticotropin-releasing factor (CRF) and corticosterone, are involved in reinstatement of alcohol seeking induced by the intermittent footshock stressor. METHDOS: 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 behavior was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 5-8 days. Reinstatement of alcohol seeking was then determined after exposure to intermittent footshock (0.8 mA; 10 min) in different groups of rats that were pretreated with CRF receptor antagonists or underwent adrenalectomy (ADX) to remove endogenous corticosterone from the body.


RESULTS
The CRF receptor antagonists, d-phe-CRF (0.3 or 1.0 microg; ICV) and CP-154,526 (15, 30 or 45 mg/kg; IP) attenuated footshock-induced reinstatement of alcohol seeking in a dose dependent manner. In contrast, the removal of circulating corticosterone by ADX had no effect on footshock stress-induced reinstatement of alcohol-taking behavior. In addition, the prevention of the footshock-induced rise in corticosterone while maintaining basal levels of the hormone by providing adrenalectomized rats with corticosterone pellets (50 mg/kg per day), had no effect on stress-induced reinstatement.


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, point to a general role of CRF in relapse to drugs induced by stressors.
Department of Neuroscience, Center for Addiction and Mental Health, Toronto, Ontario, Canada.
A D
AD
Lê
S
S
Harding
W
W
Juzytsch
J
J
Watchus
U
U
Shalev
Y
Y
Shaham
D000315:Adrenalectomy; D000437:Alcoholism / Q000523:psychology*; D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004597:Electroshock; D005108:Extinction, Psychological / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration; D013315:Stress, Psychological / Q000523:psychology*
C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone