Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys

Abstract

The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered i.v. cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it.

Rapid Assessment of Choice between Cocaine and Food in Rhesus Monkeys: Effects of Environmental Manipulations and Treatment with d-Amphetamine and Flupenthixol

“…Rather, these findings suggest that cocaine produced a nonselective decrease in the ability of the monkeys to perform the key-press responses or a nonselective decrease in the reinforcing effects of both cocaine and food. In agreement with this conclusion, previous studies that examined cocaine-and food-maintained responding independently also found that acute, noncontingent cocaine decreased high-dose cocaine selfadministration only at doses that also decreased foodmaintained responding (Glowa and Fantegrossi, 1997;Panlilio et al, 1998).…”

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

“…These data suggest that the rate of onset may play an important role in the reinforcing strength of psychomotor stimulants. Consistent with the latter interpretation, when cocaine was infused more slowly, it was found to be less effective as a reinforcer in nonhuman primates (Panlilio et al, 1998). Similarly, the cocaine analog HD-23, which takes 60 min to attain significant binding was not as reinforcing in rhesus monkeys as were cocaine or methylphenidate (Lile et al, 2003).…”

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

“…oral) resulting in slower drug uptake (Volkow et al, 2000). When cocaine was infused more slowly, it was found to be less effective as a reinforcer in nonhuman primates (Balster and Schuster, 1973;Panlilio et al, 1998). Similarly, the cocaine analog HD-23, which takes 60 min to attain significant binding was not as reinforcing in rhesus monkeys as were cocaine or methylphenidate (Lile et al, 2003).…”