Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action.
BACKGROUND
Abuse of drug mixtures is common. Drug interactions that are super-additive in terms of reinforcing effects may contribute to this phenomenon. Although quantitative methods for assessing drug interactions have been developed, they have not been widely applied to the analysis of reinforcing effects.


OBJECTIVE
The present experiment was designed to study self-administration of mixtures of drugs with comparable pharmacological mechanisms of action. Our hypothesis was that the drugs would be dose-additive.


METHODS
Rhesus monkeys prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule in baseline sessions. When responding was stable, two mu opioid agonists, alfentanil and remifentanil, were tested alone in one group (n = 5). Two dopamine (DA) uptake blockers, cocaine and RTI-117 were tested in the other group (n = 6). Next, mixtures of doses of the two opioids or the two DA uptake blockers were tested in approximate 1:1, 1:2, and 2:1 ratios of their ED50s. Results were analyzed using isobolographic techniques.


RESULTS
All drugs alone and drug mixtures functioned as positive reinforcers in a dose-related manner. There was no difference between experimentally determined ED50 values and predicted additive ED50 values for any mixture. Maximum responding maintained by mixtures, a measure of reinforcing strength, did not differ from that for single drugs.


CONCLUSIONS
Mixtures of various proportions of two drugs with comparable mechanisms of action were additive, i.e., they did not interact. This result will serve as the basis for comparison to studies of mixtures of drugs with various mechanisms of action.
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
Carroll
F Ivy
FI
Tallarida
Ronald
R
D015760:Alfentanil / Q000008:administration & dosage / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D008253:Macaca mulatta; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D000077208:Remifentanil; D012646:Self Administration
D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D004338:Drug Combinations; D010880:Piperidines; C121918:RTI 117; D015760:Alfentanil; D003042:Cocaine; D000077208:Remifentanil