Characteristics of tolerance, recovery from tolerance and cross-tolerance for cocaine used as a discriminative stimulus.

Rats were trained to discriminate an injection of cocaine (10 mg/kg) from saline using a two-lever choice procedure with food as a reinforcer. Subsequently, training was stopped, and cocaine was injected chronically. In one experiment, 10.0 or 20.0 mg/kg/8 hr 8 hr of cocaine for 7 days produced a 2-fold shift to the right of the discriminative stimulus dose-effect curve. A dose of 5.0 mg/kg/8 hr for up to 14 days did not shift the dose-effect curve. In a second experiment, 20 mg/kg/8 hr for 7 or 14 days produced comparable degrees of tolerance. In a third experiment, after termination of 12 days of chronic cocaine injection (20 mg/kg/8 hr), base-line sensitivity to the training stimulus recovered progressively across 18 days. Additional experiments tested the effects of chronic administration of drugs that were substituted (d-amphetamine) or were not substituted (morphine) for the training stimulus. d-Amphetamine (2.5 mg/kg/8 hr for 7 days) produced a 4-fold shift to the right of the dose-effect curve for the detection of both d-amphetamine and cocaine; in contrast, 7 days of escalating morphine doses produced signs of physical dependence but did not alter the sensitivity of rats to the cocaine training stimulus. These results provide evidence that tolerance for cocaine used as a discriminative stimulus occurs as a function of chronic dose, dosing regimen and class of drug administered.