Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine.
BACKGROUND
Ketoconazole (Keto) is an antifungal agent that also inhibits the synthesis of adrenocorticosteroids and has been reported to act as a glucocorticoid receptor antagonist.


OBJECTIVE
The present experiments investigated the effects of Keto on the stressor-induced reinstatement of extinguished cocaine-seeking behavior and on the generalization of a stressor-induced discriminative stimulus to cocaine in rats.


METHODS
In the first experiment, male Wistar rats were trained to self-administer cocaine (0.5 mg/kg per infusion, IV) under a fixed-ratio 4 schedule of reinforcement with a 90-s limited hold. Following ten consecutive extinction sessions, the effects of Keto (25 or 50 mg/kg, IP) or vehicle on the ability of EFS (electric footshock; 15 min) to reinstate extinguished cocaine-lever responding were investigated. In the second experiment, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, food-reinforced drug discrimination design. The effects of Keto (50 mg/kg, IP) or vehicle on the EFS-induced generalization to cocaine were determined.


RESULTS
EFS reinstated extinguished cocaine- but not food-reinforced responding. Keto (25 and 50 mg/kg, IP) blocked the EFS-induced reinstatement of cocaine-seeking behavior and significantly attenuated the plasma corticosterone response to EFS. These same doses of Keto failed to affect responding in rats trained to self-administer food pellets under an FR4 schedule of reinforcement. EFS also produced significant cocaine-appropriate responding in rats trained to discriminate the drug from saline. However, Keto (50 mg/kg) failed to block the EFS-induced generalization to cocaine.


CONCLUSIONS
Overall, these data suggest that corticosterone contributes to the stressor-induced reinstatement of extinguished cocaine-seeking behavior.
Mantsch
J R
JR
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Goeders
N E
NE
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D003345:Corticosterone / Q000097:blood; D004193:Discrimination Learning / Q000187:drug effects*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration; D013315:Stress, Psychological / Q000523:psychology*
D000935:Antifungal Agents; D003042:Cocaine; D007654:Ketoconazole; D003345:Corticosterone