Tolerance and cross-tolerance to cocaine and d-amphetamine.

The effects of cocaine (4.0-32 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) on milk intake of rats were determined before and during periods of repeated daily administration of each drug. Experimental sessions consisted of 15 minutes access to 50 ml of a sweetened condensed milk solution. After the determination of the disruptive effects of single injections of cocaine or d-amphetamine on milk intake, rats were injected daily with either 16 mg/kg of cocaine 15 minutes before the session, 16 mg/kg of cocaine immediately after the session, 2.0 mg/kg of d-amphetamine 15 minutes before the session or saline before the session. During the period of repeated administration when milk intake had stabilized in each group, dose-effect functions for cocaine and d-amphetamine on milk intake were redetermined. On selected days, test doses of either drug were substituted for the usual daily injection. Test doses were separated by at least 3 days of stable intake after injection of the appropriate drug or saline. During the period of repeated administration, milk intake returned toward control levels for animals receiving daily cocaine or daily d-amphetamine before the session. Further, when the dose-effect functions for cocaine and d-amphetamine on milk intake were redetermined, a shift to the right (i.e., toward larger doses) was observed in all groups that had received drug presession during the repeated administration. This indicates that the animals became tolerant to cocaine and d-amphetamine as well as cross-tolerant to both drugs. The development of tolerance to cocaine was contingent upon the relationship of the time of injection to milk availability. Animals that had received postsession injections of cocaine during repeated administration were more sensitive to the effects of cocaine and d-amphetamine on milk intake.