Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats.
BACKGROUND
Ketoconazole, an inhibitor of corticosterone synthesis, has been reported to decrease the self-administration of low doses of cocaine and prevent stress-induced reinstatement of cocaine-reinforced behavior in rats.


OBJECTIVE
The effects of ketoconazole were extended to the acquisition of i.v. cocaine self-administration during food restriction, a form of stress. Food restriction accelerates the acquisition of cocaine self-administration, and the purpose of this experiment was to determine whether ketoconazole would block the food-restriction effect. As control conditions, the effects of ketoconazole on the acquisition of cocaine self-administration in food-satiated rats and acquisition of food-reinforced responding were also evaluated.


METHODS
Six groups of rats (groups 1-6) were trained to self-administer i.v. cocaine (0.2 mg/kg; groups 1-4) or food pellets (45 mg; groups 5 and 6) under a fixed-ratio 1 (FR 1) schedule. Food availability was restricted to 20 g per day in groups 1, 2, 5, and 6, while groups 3 and 4 were fed ad libitum. Daily sessions included a 6-h autoshaping component followed by a 6-h self-administration component. During autoshaping, 10 infusions or food pellets were delivered each h under a random interval 15-s schedule after extension and retraction of a lever. During self-administration, the lever remained extended and infusions or food pellets were available under an FR 1 schedule. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions or 150 food pellets was obtained during the self-administration component. Rats were given 30 days to reach this criterion. They were pretreated with ketoconazole (25 mg/kg, i.p.; groups 1, 3, and 5) or vehicle (i.p.; groups 2, 4, and 6) 30 min prior to the autoshaping and self-administration components.


RESULTS
Pretreatment with ketoconazole decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion but only under food-restricted conditions. Ketoconazole had no effect on the acquisition of food-reinforced responding.


CONCLUSIONS
These results extended previous findings of the suppressant effects of ketoconazole on cocaine-reinforced responding in rats to the acquisition of cocaine self-administration using food restriction as a stressor.
Campbell
U C
UC
Department of Psychiatry, University of Minnesota Medical School, UMHC, Box 392, Minneapolis, MN 55455, USA.
Carroll
M E
ME
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000523:psychology; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005508:Food Deprivation / Q000502:physiology; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012527:Satiation / Q000502:physiology; D012646:Self Administration / Q000523:psychology
D000935:Antifungal Agents; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D007654:Ketoconazole