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. doi: 10.1007/s002130050905.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology*
  • Cocaine / administration & dosage*
  • Corticosterone / blood
  • Discrimination Learning / drug effects*
  • Ketoconazole / pharmacology*
  • Male
  • Rats
  • Rats, Wistar
  • Reinforcement Schedule
  • Self Administration
  • Stress, Psychological / psychology*


  • Antifungal Agents
  • Cocaine
  • Ketoconazole
  • Corticosterone