Chronic d-amphetamine or methamphetamine produces cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine

These experiments tested the hypothesis that chronic administration of d-amphetamine (d-A) or methamphetamine (METH) would produce cross-tolerance to the discriminative and/or reinforcing effects of cocaine. One group of rats (n = 20) was trained to detect cocaine (10.0 mg/kg; i.p.) from vehicle; cocaine (1.0-17.8 mg/kg) dose dependently substituted for the training dose. Chronic administration of d-A or METH (0.32, 1.0 and 3.2 mg/kg/12 hr for 7 days) resulted in cross-tolerance to the discriminative stimulus effects of cocaine. A second group of rats (n = 12) was implanted with indwelling jugular catheters and were trained to self-administer cocaine under a fixed- ratio 2 schedule of reinforcement. This group of rats also received chronic d-A or METH (0.32, 1.0 and 3.2 mg/kg/12 hr for 7 days). In this group, chronic administration of the highest dose of d-A and of METH (3.2 mg/kg) resulted in cross-tolerance to the self-administration of cocaine. A third group of rats (n = 15) was implanted with indwelling jugular catheters and were trained to self-administer cocaine under a progressive-ratio schedule of reinforcement. Chronic administration of d-A and METH (3.2 mg/kg/12 hr for 7 days) resulted in cross-tolerance to the self-administration of cocaine under this progressive-ratio schedule. The data obtained from these experiments demonstrate that chronic treatment with central nervous system stimulants of the amphetamine type (d-A or METH) produces cross-tolerance to both the discriminative and reinforcing effects of cocaine.