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


OBJECTIVE
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.


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.
Woolverton
W L
WL
Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA. wwoolverton@psychiatry.umsmed.edu
Wang
Zhixia
Z
Vasterling
Theresa
T
Tallarida
Ronald
R
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008253:Macaca mulatta; D008297:Male; D009293:Opioid-Related Disorders / Q000523:psychology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D012044:Regression Analysis; D000077208:Remifentanil; D012646:Self Administration; D019966:Substance-Related Disorders / Q000523:psychology*
D000701:Analgesics, Opioid; D004338:Drug Combinations; D010880:Piperidines; D003042:Cocaine; D000077208:Remifentanil