Abstract
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 pKB 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.
Footnotes
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Send reprint requests to: Dr. James K. Rowlett, Harvard Medical School, New England Regional Primate Research Center, Box 9102, One Pine Hill Drive, Southborough, MA 01772-9102.
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↵1 This work was supported by National Institute on Drug Abuse Grant DA10352 (W.L.W.) and National Research Scientist Award DA05625 (J.K.R.). The animals used in this study were maintained in accordance with the United States Public Health Service “Guide for Care and Use of Laboratory Animals” and all procedures were approved by the University of Mississippi Medical Center Institutional Animal Care and Use Committee.
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↵2 Current address: Harvard Medical School, New England Regional Primate Research Center, Box 9102, One Pine Hill Drive, Southborough, MA 01772-9102.
- Abbreviations:
- AIDS
- acquired-immune deficiency syndrome
- CI
- confidence interval
- ED50
- dose that produced 50% of the maximum injections/session produced by drug alone
- FR
- fixed-ratio
- Imax
- maximum injections/session, reinforcing efficacy
- LH
- limited hold
- PR
- progressive-ratio
- TO
- time-out
- Received October 24, 1997.
- Accepted March 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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