Effects of continuous cocaine administration on schedule-controlled behavior in rhesus monkeys.

The behavioral effects of continuous infusion of cocaine for prolonged periods were examined in rhesus monkeys responding under fixed-ratio (FR) or fixed-interval (FI) schedules of food presentation. Operant behavior was examined every 6h for 30min (FR) or 60min (FI) while saline or increasing doses of cocaine (4.0-32mg/kg/day) were continuously (24h/day) infused through an intravenous catheter. Cocaine initially reduced FR responding and tolerance developed to doses as high as 32mg/kg/day over periods of 10 to 35 days. When continuous infusion of cocaine (32mg/kg/day) was terminated after 50-80 total days of cocaine exposure, behavior was disrupted for several days in three of four monkeys. These behavioral disruptions were reversed when cocaine (0.062-0.25mg/kg) was administered i.v. 10min before sessions in which responding was typically suppressed, suggesting that behavioral dependence on cocaine had developed. Continuous infusion of cocaine also initially decreased the rate of FI 60s responding and tolerance developed to doses of 4.0 and 8.0mg/kg/day. Behavioral disruptions were not consistently observed when infusion of cocaine (8.0mg/kg/day) was terminated after up to 110 total days of cocaine exposure. Although reinforcement loss was comparable under the two schedules of reinforcement, the rate and extent of tolerance development varied between the two schedules of reinforcement. Therefore, behavioral factors in addition to reinforcement loss contribute to the development of cocaine tolerance. In addition, the data suggest that behavioral dependence upon cocaine can develop, but only under extreme exposure conditions.