Vol. 286, Issue 1, 61-69, July 1998

Self-Administration of Cocaine-Heroin Combinations by Rhesus Monkeys: Antagonism by Naltrexone¹

James K. Rowlett² , Kristin M. Wilcox and William L. Woolverton

Department of Psychiatry and Human Behavior (J.K.R, K.M.W, W.L.W.), Department of Pharmacology and Toxicology (K.M.W., W.L.W.), University of Mississippi Medical Center, Jackson, Mississippi

Low, nonreinforcing doses of heroin have been shown to shift the dose-response function of cocaine leftward in rhesus monkeys trained under a progressive-ratio schedule of i.v. drug injection. Our study sought to determine 1) whether a reciprocal enhancement of heroin self-administration would be observed when heroin was combined with low, nonreinforcing doses of cocaine, and 2) whether self-administration of cocaine-heroin combinations could be antagonized by the opioid antagonist naltrexone. Rhesus monkeys (n = 4) were prepared with i.v. catheters and trained to self-administer cocaine under a progressive-ratio schedule. The initial response requirement of this schedule was fixed-ratio 120, which doubled across the session to a maximum of 1920. Injections were separated by a 30-min time out. Cocaine dose-response functions (6.4-100 µg/kg/injection) for injections/session and breakpoints were monophasic, i.e., increased with dose until responding reached a maximum. Heroin dose-response functions (1.6-25 µg/kg/injection) either increased to a peak and then decreased or reached an asymptote. When nonreinforcing doses of cocaine (3.2-25 µg/kg/injection) were combined with heroin, the heroin dose-response function was shifted to the left, without change in maximum injections/session. Presession treatments with naltrexone (3.2-1600 µg/kg, i.m., 10-min presession) antagonized self-administration of heroin and heroin + cocaine combinations in a dose-dependent fashion. However, naltrexone treatment had no effect on cocaine self-administration. Antagonism by naltrexone of self-administration of heroin and heroin + cocaine was surmounted by increasing the dose of heroin either alone or in the heroin + cocaine combination. In vivo apparent pA₂ and pK_B analyses of these data revealed values of approximately 8.0, consistent with a role for mu opioid receptors in the self-administration of heroin and cocaineheroin (i.e., "speedball") combinations.