Cocaine self-administration under variable-dose schedules in squirrel monkeys

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Abstract

Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration. However, drug intake eventually became “dysregulated” after extensive training (100–300 sessions), with relatively short pauses following all doses. Dose-sensitivity was restored by adding a 60-s timeout period after each injection, suggesting that dysregulation occurred because the monkeys developed a tendency to self-administer another injection before the previous injection had been adequately distributed. Finally, when the response requirement under the variable-dose schedule was increased from 1 to 10, both the post-injection pause and the rate of responding following the pause (“run rates”) were found to vary with dose. The dose-dependency of run rates suggests that post-injection pauses reflect not only motivational factors, such as satiety, but also the direct effects of cocaine on leverpressing.

Section snippets

Subjects

Three adult male squirrel monkeys (Saimiri sciureus) weighing 850–1100 g were housed in individual cages in rooms with light, temperature and humidity controlled. Fresh water was continuously available in the home cage. The monkeys were provided daily with five biscuits of high protein monkey diet (Lab Diet 5045; PMI Nutrition International, Richmond, Ind., USA) and two pieces of Banana Softies (Bio-Serv, Frenchtown, N.J., USA), and they also received fresh fruits or vegetables daily as part of

Initial training and effects of treatment with SCH 23390

Dose-dependent responding developed in all three monkeys during the initial phase of training, with consistent behavior observed both within and between subjects (see “baseline” data in Fig. 1). The highest dose of cocaine (300 μg/kg) began to produce longer latencies than the lower doses within the first few sessions for all three monkeys. Latencies following the second highest dose (100 μg/kg) did not become differentiated from the two lowest doses until about the 20th session in two monkeys,

Regulation of drug intake

The variable-dose schedule of cocaine self-administration produced orderly within-session dose–effect curves for cocaine, and these curves were shifted to the right by acute treatment with a dopaminergic antagonist. However, behavior became less sensitive to the injection dose after extended training. This loss of dose-sensitivity appears to have been due to a tendency to self-administer another injection before the previous injection had been adequately distributed to the brain. Addition of a

Acknowledgement

This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse.

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