Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine. Psychopharmacology (Berl) 1999 Mar;142(4):399-407
Date
05/06/1999Pubmed ID
10229065DOI
10.1007/s002130050905Scopus ID
2-s2.0-0032893173 (requires institutional sign-in at Scopus site) 100 CitationsAbstract
RATIONALE: 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.
Author List
Mantsch JR, Goeders NEAuthor
John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntifungal Agents
Cocaine
Corticosterone
Discrimination Learning
Ketoconazole
Male
Rats
Rats, Wistar
Reinforcement Schedule
Self Administration
Stress, Psychological
