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In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.

Four squirrel monkeys responded daily under a fixed-interval 5-min or 8-min schedule of food-pellet delivery. Cocaine (0.03 to 1.7 mg/kg) and saline were injected before occasional daily sessions (acute administration). Some doses of cocaine produced substantial overall increases in response rate for 3 of the subjects; effects were less substantial for the remaining subject, who exhibited modest increases in response rate early in the session and during the middle portion of the intervals. A dose that increased response rate when administered acutely was then administered before each session (chronic administration). Chronic administration resulted in a reduction in the increases in response rate seen under acute administration for all subjects.Key words: fixed-interval schedules, cocaine, behavioral tolerance, lever press, squirrel monkeyBehavioral effects of repeated cocaine exposure depend on many factors. An early report by Tatum and Seevers (1929) that after repeated exposure, behavior can become more sensitive to the drug has been confirmed by others (Post & Rose, 1976; Woolverton, Kandel, & Schuster, 1978b). In contrast to studies reporting sensitization, other research shows that behavior can become less sensitive to cocaine (tolerance) after repeated administration (e.g., Branch & Sizemore, 1988;Moore & Thompson, 1978;Woolverton et al., 1978b;Woolverton, Kandel, & Schuster, 1978a fects of 1.0 mg/kg d-amphetamine when reinforcement rate was initially disrupted during a schedule that reinforced interresponse times greater than 30 s (Schuster, Dockens, & Woods, 1966). However, tolerance to rate-increasing effects did not occur when reinforcement rate was not disrupted under a fixed-interval (FI) 30-s schedule. Thus, the effects of repeated administration of d-amphetamine depended on its initial effects on reinforcement rate. This has become known as the reinforcement-loss hypothesis, and has been applied to drugs other than amphetamines, including cocaine (Moore & Thompson, 1978;Woolverton et al., 1978aWoolverton et al., , 1978b.Although interactions between the behavioral effects of drugs and the consequences of behavior have been shown to be important (Smith & McKearney, 1977;van Haaren, 1992), the lack of tolerance to stimulant-induced rate increases on FT performance reported by Schuster et al. (1966) is not a consistent finding. One additional study found little change in cocaine's rate-increasing effects on FI shock-termination responding of squirrel monkeys when the drug was infused continuously (0.1 and 0.3 mg/kg/hr) for 2 weeks (Howell & Morse, 1989). However, reduction in initial rate increases has been reported after studying 0.16 mg/kg d-amphetamine and 0.5 mg/kg 1-amphetamine on FI food-maintained responding of rats (Tilson & Sparber, 1973), and after studying effects of 0.1 mg/kg d-amphetamine on FI responding of squirrel monkeys maintained by food delivery, shock termination, or shock delivery (Branch, 1979) when drugs were administered once daily before sessions. Thus, studies that have pr...

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