Effect of repeated administration of various doses of cocaine and WIN 35,065-2 on locomotor behavior of mice.

Cocaine and a cocaine analog, WIN 36,065-2, were administered daily for 3 or 4 days. Both compounds developed sensitization to their locomotor stimulatory effects, with similarly shaped dose-response curves. Dosages giving optimal sensitization were 25 mg/kg per day for cocaine and 3 mg/kg for WIN 35,065-2. At 40 mg/kg, cocaine produced less stimulation of locomotion on day 3 than on day 1. With doses of 6 and 10 mg/kg of WIN 35,065-2, tolerance to locomotor stimulation was observed. Monitoring by an observer revealed that after 40 mg/kg of cocaine the animals spent about the same amount of time expressing non-ambulatory behavior such as biting, sniffing, rearing, or resting on day 3 as on day 1. Therefore, in the 3 day period there was no increase in non-ambulatory behavior that could have produced the decrease in locomotor stimulation measured with the activity monitor. We assessed the possible involvement of the local anesthetic action of cocaine-like compounds in inhibiting locomotion by measuring the hypomotive effect over a 3 day period by repeated administration of the local anesthetic drugs tetracaine, lidocaine, norcocaine and benzoylpseudotropine. These compounds had the same hypomotive effects on day 1 and 3, suggesting that the decrements in locomotor stimulation observed with daily high doses of cocaine and WIN 35,065-2 involve mechanisms other than their local anesthetic action. The present results indicate that the size of the dose of a psychostimulant is a crucial variable in dosage schedules for studying the sensitization to its effect on locomotor behavior.