Self-administration of cocaine and remifentanil by monkeys: choice between single drugs and mixtures

Abstract

Rationale: Cocaine and opioids are often co-abused. As yet, however, there is no clear evidence that the drugs interact to make the mixture a more effective reinforcer.

Objective: The present study examined the relative reinforcing potency and maximum effectiveness of the cocaine-opioid combination in monkeys given a choice between cocaine-opioid mixtures and the single-component drugs.

Method: Rhesus monkeys were allowed to choose between injections of cocaine (100 μg/kg/inj) and other doses of cocaine (10-560 μg/kg/inj) or remifentanil (0.03-3.0 μg/kg/inj). A dose-addition model was used to select dose combinations for mixtures of cocaine and remifentanil predicted to be equivalent to 100 μg/kg/inj of cocaine in reinforcing effect if the drugs were additive. The monkeys were then allowed to choose between (a) cocaine and mixtures predicted to be equivalent to 100 μg/kg/inj of cocaine, (b) increasing doses of the mixtures and the single-component drugs, and (c) cocaine or remifentanil at doses that were in the highest safe range.

Results: Generally, monkeys preferred the mixtures over 100 μg/kg/inj of cocaine, evidence for superadditivity. However, preferences for the mixture ceased when relatively high doses of single-component drugs were offered as alternatives. When doses within the mixture were raised and offered with relatively high doses of the single drugs, there was no clear preference for either option. The highest dose of remifentanil was chosen over the highest dose of cocaine by all monkeys.

Conclusion: The current results indicate that cocaine-opioid combinations can be super-additive in terms of potency, but are not, at maximum, more effective than the single-component drugs.

Fig. 1

Choice options for each phase of the study. Cocaine, Coc; remifentanil, Remi

Fig. 2

Dose–response functions for cocaine and remifentanil choice in each of six monkeys when 100 μg/kg/inj of cocaine was the alternative. Each data point is the average of three stable sessions with lever reversals, for a total of six sessions. Numbers on the abscissa represent drug dose (μg/kg/inj) of cocaine or remifentanil. Numbers on the ordinate represent percent choice for various doses of cocaine and remifentanil when 100 μg/kg/inj of cocaine was the alternative

Fig. 3

Percent choice in four monkeys for three mixture ratios of cocaine/remifentanil predicted to be equivalent in reinforcing effect to 100 μg/kg/inj of cocaine if the drugs were additive. The alternatives to the mixtures were cocaine at 100 μg/kg/inj (Coc 100; black bars), 300 μg/kg/inj (Coc 300; dark gray bars) or 560 μg/kg/inj (Coc 560; light gray bars), and remifentanil at 1.0 μg/kg/inj (Remi 1.0; horizontally hatched bars) or 1.7 μg/kg/inj (Remi 1.7; diagonally hatched bars). Missing bars indicate conditions that were not run, not zero percent choice

Fig. 4

Percent choice in four monkeys for 1:1 and 2:2 mixtures of cocaine/remifentanil when cocaine was offered as an alternative at 100 μg/kg/inj (Coc 100; black bars) or 560 μg/kg/inj (Coc 560; gray bars) and remifentanil at 1.7 μg/kg/inj (Remi 1.7; diagonally hatched bars)