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.

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions

“…For the remaining three subjects, weights ranged from 9.5–10.6 kg at the beginning of the study. DJ9J and DK12 had a history of self-administration of cocaine and remifentanil mixtures (Freeman and Woolverton 2011). RO2050 had a history with drug self-administration under PR and fixed-ratio (FR) schedules, and most recently with cocaine and nicotine mixtures (Freeman and Woolverton 2009).…”

“…catheter implanted according to previous protocols (e.g., Freeman and Woolverton 2011). Monkeys were injected with atropine sulfate (0.04 mg/kg i.m.)…”

“…Maximum choice reached similar asymptotes for the mixture and each of the single drugs, and Negus (2005) reported that cocaine-heroin mixtures were more potent, but not more effective reinforcers than either of the drugs alone. With drug-vs-drug choice, where choice was between cocaine-opioid mixtures versus one of the single drugs, the mixtures were generally chosen over the single drugs (Freeman and Woolverton 2011; Ward et al 2005; Wang et al 2001). However, choice for the mixture could be overcome by increasing the dose of the single-drug option (Freeman and Woolverton 2011).…”

“…With drug-vs-drug choice, where choice was between cocaine-opioid mixtures versus one of the single drugs, the mixtures were generally chosen over the single drugs (Freeman and Woolverton 2011; Ward et al 2005; Wang et al 2001). However, choice for the mixture could be overcome by increasing the dose of the single-drug option (Freeman and Woolverton 2011). Thus, cocaine-opioid mixtures were more potent reinforcers than the single drugs, but at maximally effective doses, the mixtures were not more effective reinforcers (Freeman and Woolverton 2011; Negus 2005; Ward et al 2005; Wang et al 2001).…”

“…However, choice for the mixture could be overcome by increasing the dose of the single-drug option (Freeman and Woolverton 2011). Thus, cocaine-opioid mixtures were more potent reinforcers than the single drugs, but at maximally effective doses, the mixtures were not more effective reinforcers (Freeman and Woolverton 2011; Negus 2005; Ward et al 2005; Wang et al 2001). …”