, Volume 142, Issue 4, pp 399–407

Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine

  • J. R. Mantsch
  • N. E. Goeders

DOI: 10.1007/s002130050905

Cite this article as:
Mantsch, J. & Goeders, N. Psychopharmacology (1999) 142: 399. 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.

Key words Cocaine Self-administration Stress Reinstatement Corticosterone Drug discrimination Ketoconazole 

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • J. R. Mantsch
    • 1
  • N. E. Goeders
    • 1
  1. 1.Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, P.O. Box 33932, 1501 Kings Highway, Shreveport, LA 71130-3932, USA, e-mail:, Fax: +1-318-675-7857US
  2. 2.Department of Psychiatry, Louisiana State University Medical Center, Shreveport, LA 71130-3932, USAUS

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