Acquisition and recovery of tolerance to the discriminative stimulus properties of cocaine.

Rats were trained to discriminate the stimulus properties of cocaine using a two-lever choice paradigm, in which food reinforcement was delivered for responses on the correct lever: one lever was always correct after a 5 mg/kg injection of cocaine, and the other lever was always correct after an injection of saline. After training, administration of cocaine and methamphetamine were generalized to the cocaine lever in a dose-dependent fashion, but administration of phenylethylamine was only partially generalized. Training was then suspended, and cocaine (20 mg/kg) was injected every 8 hr. Tolerance developed progressively to the discriminative stimulus properties of cocaine. After six days of chronic administration, redetermination of dose-effect data showed the presence of tolerance and cross-tolerance to the stimulus properties of cocaine and methamphetamine, respectively, with no evidence for cross-tolerance to phenylethylamine. No tolerance or sensitization developed to the suppressant effects of cocaine on operant responding. After termination of the chronic administration of cocaine, the tolerance was lost at the same rate at which it was acquired. These data demonstrate that tolerance occurs to the stimulus properties of cocaine and suggests that a common mechanism mediates the stimulus properties of cocaine and methamphetamine.