Ketoconazole Does Not Block Cocaine Discrimination or the Cocaine-Induced Reinstatement of Cocaine-Seeking Behavior

doi:10.1016/S0091-3057(99)00090-8

Pharmacology Biochemistry and Behavior

Volume 64, Issue 1, September 1999, Pages 65-73

https://doi.org/10.1016/S0091-3057(99)00090-8 Get rights and content

Abstract

Ketoconazole is an FDA-approved antifungal agent that also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. It has been previously demonstrated that this drug blocks the stress-induced reinstatement of cocaine-seeking behavior and reduces low-dose cocaine self-administration in rats. In the present experiments, the effects of ketoconazole on the cocaine-induced reinstatement of extinguished cocaine-seeking behavior and on cocaine discrimination were investigated in male Wistar rats. In rats trained to self-administer cocaine (0.5 mg/kg/infusion) by pressing a lever under a fixed-ratio 4 schedule of reinforcement, cocaine (5–20 mg/kg, IP) dose dependently reinstated cocaine-seeking behavior following at least 10 days of extinction, during which responding on the cocaine lever resulted in no programmed consequences. Ketoconazole (50 mg/kg, IP) failed to block cocaine-induced reinstatement despite blocking cocaine-induced increases in plasma corticosterone. Ketoconazole (25 or 50 mg/kg) also failed to block cocaine discrimination in rats trained to discriminate 10 mg/kg cocaine from saline. In these rats, generalization to the training dose of cocaine was observed in the absence of increases in plasma corticosterone. The results of these experiments indicate that corticosterone may mediate the effects of stressors on cocaine-seeking behavior but not the direct effects of cocaine itself.

Section snippets

Subjects

Thirty-six male Wistar rats (Harlan–Sprague–Dawley, Indianapolis, IN), 80 to 100 days old at the start of the experiments, were used. All rats were housed individually in cages equipped with a laminar flow unit and air filter in a temperature- and humidity-controlled, AAALAC-accredited animal care facility on a reversed 12L:12D cycle (lights on at 1800 h). Rats were maintained at 85 to 90% of their preexperimental free-feeding body weights by presentations of food pellets (P. J. Noyes,

Results

Rats rapidly acquired cocaine self-administration and began responding under an FR4 schedule of reinforcement after a mean of 11.26 (±0.66) sessions. The extinction of cocaine self-administration is shown in Fig. 1. A one-way ANOVA revealed a significant extinction effect, F (9, 162) = 59.568, p < 0.0001. The total numbers of responses emitted during all extinction sessions were significantly less than during the final self-administration session prior to extinction (p < 0.001). Additionally,

Discussion

In the present experiments, KETO failed to block the cocaine-induced reinstatement of extinguished cocaine-seeking behavior, and did not attenuate cocaine discrimination in rats trained to discriminate the drug from saline. The doses of KETO used in these experiments (i.e., 25 and 50 mg/kg) have previously been demonstrated to block EFS-induced reinstatement (24) and to reduce low-dose cocaine self-administration in rats (18). Together, these findings indicate that there is a distinction

Acknowledgements

The authors gratefully acknowledge G. F. Guerin for his expert technical assistance and invaluable advice. This work was supported by United States Public Health Service grants DA06013 and DA05836 from the National Institute on Drug Abuse.

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¹: Current address: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Ave., New York, NY 10021.

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ArticlesKetoconazole Does Not Block Cocaine Discrimination or the Cocaine-Induced Reinstatement of Cocaine-Seeking Behavior

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgements

Pharmacol. Biochem. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Psychoneuroendocrinology

Trends Pharmacol. Sci.

Peptides

Brain Res.

Brain Res.

Cocaine- but not food-seeking behavior is reinstated by stress after extinction

Psychopharmacology (Berlin)

Classification of drugs according to their discriminable effects in rats

Fed. Proc.

Antifungal agents

Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine

Psychopharmacology (Berlin)

Effects of buprenorphine and naltrexone on reinstatement of cocaine-reinforced responding in rats

J. Pharmacol. Exp. Ther.

Glucocorticoids and behavioral effects of psychostimulants. II.Cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels

J. Pharmacol. Exp. Ther.

Conditioned release of corticosterone by contextual stimuli associated with cocaine is mediated by corticotropin-releasing factor

Brain Res.

Reinstatement of cocaine-reinforced responding in the rat

Psychopharmacology (Berlin)

Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period

Psychopharmacology (Berlin)

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

J. Neurosci.

Articles
Ketoconazole Does Not Block Cocaine Discrimination or the Cocaine-Induced Reinstatement of Cocaine-Seeking Behavior