Self-administration of cocaine-remifentanil mixtures by monkeys: an isobolographic analysis

Abstract

Rationale: Abuse of mixtures of stimulants and opioids ("speedball") is common. Although this combination has been studied in the laboratory, conclusions about the nature of the cocaine/opioid interaction have been mixed.

Objectives: The objectives of the present experiment were to allow monkeys to self-administer mixtures of cocaine and the mu opioid agonist remifentanil and to quantify the interaction using the isobolographic approach. Our hypothesis was that the drugs would be super-additive in their reinforcing effects.

Materials and methods: Rhesus monkeys (n = 5) prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule. When responding was stable, doses of cocaine or remifentanil were made available in test sessions. Next, mixtures of doses of the drugs were tested over a range of doses in 1:1, 1:2, and 2:1 ratios of their ED(50)s. Results were analyzed using isobolographic techniques.

Results: Both drugs alone and all drug mixtures functioned as positive reinforcers in a dose-related manner. Cocaine maintained more responding at maximum than did remifentanil, i.e., was a stronger reinforcer. The experimentally determined equi-effective dose for the 1:1 and 1:2 cocaine/remifentanil mixtures tended toward super-additivity, but the difference from additivity did not achieve statistical significance. The 2:1 mixture was super-additive. Maximum responding maintained by the mixtures was higher than that maintained by remifentanil but not different from cocaine.

Conclusions: Combinations of cocaine and remifentanil can be additive or super-additive as positive reinforcers, depending on proportions of each. Interactions between stimulants and opioids may contribute to the abuse of these mixtures.

Fig. 1

Constructing the isobole for drug A and drug B. The graph illustrates how dose pairs (a, b) define the additive isobole for the selected effect. To achieve the selected effect level (e.g., ten injections per session), consider an arbitrary dose a of drug A (point 1). This dose has a drug B-equivalent, b_eq (point 2). Either dose alone would produce an effect that is less than the selected effect. To achieve the selected effect, one needs to add to dose a of drug A a dose b of drug B indicated by the dose interval labeled b, the difference between the doses at points 3 and 2. The set of dose pairs (a, b) defined in this way are the doses that would be predicted to have the selected effect if the drugs were dose-additive. The population of these pairs defines the isobole. If the potency ratio is constant, the isobole is a straight line. If not, the isobole is curved. In either case, it is a curve (or line) of dose pairs predicted to have the selected effect if the drugs were additive. Its equation is given by Grabovsky and Tallarida (2004)

Fig. 2

Self-administration of cocaine and remifentanil by monkeys responding under a PR schedule of reinforcement. Each data point represents the mean injections per session of each dose for two to five monkeys. Vertical lines represent SEM

Fig. 3

Isobologram representing the self-administration of mixtures of remifentanil (abscissa) and cocaine (ordinate). The solid line connects the ED₅₀ of cocaine alone to the remifentanil dose calculated to have the same effect as the ED₅₀ of cocaine. This curve represents combinations of doses that would be predicted to have this same effect if the drugs were additive, i.e., the additive isobole. Dashed radial lines (I, II, III) represent the three different cocaine/remifentanil dose ratios that were tested. Symbols on the radial lines represent the additive (on the additive line) and the experimentally determined equi-effective doses of those mixtures. The horizontal and vertical lines through these points represent the SEM8