Ketoconazole reduces low dose cocaine self-administration in rats

Ketoconazole is an oral antimycotic agent approved by the FDA for the treatment of fungal disease which also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0.5 mg/kg per infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125-0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding. In fact, pretreatment with ketoconazole resulted in rates and patterns of self-administration at these doses that were indistinguishable from those observed during cocaine extinction. However, cocaine self-administration at the highest dose tested in these experiments (i.e. 0.5 mg/kg per infusion) was not significantly affected by ketoconazole. These data suggest the potential utility of ketoconazole or related drugs as adjuncts in the treatment of cocaine abuse and further underscore the role for corticosterone in cocaine reinforcement.