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Intravenous self-administration of etonitazene alone and combined with cocaine in rhesus monkeys: comparison with heroin and antagonism by naltrexone and naloxonazine

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Abstract

Rationale

In humans, μ opioid–cocaine combinations (speedballs) have been reported to heighten pleasurable effects and result in greater abuse potential compared to either drug individually. Emerging evidence in animals suggests that the ability of μ opioids to enhance the reinforcing effects of cocaine might be independent of their μ intrinsic efficacy even though μ agonist efficacy appears to be a determinant in the reinforcing effects of μ opioids themselves.

Objectives

This study examined the relationship between agonist efficacy, self-administration, and the enhancement of cocaine self-administration using the high-efficacy μ agonist etonitazene.

Materials and methods

Rhesus monkeys self-administered cocaine, heroin, etonitazene, and opioid–cocaine combinations under a progressive-ratio schedule of intravenous drug injection.

Results

Unlike cocaine and heroin, etonitazene did not maintain consistent self-administration at any dose tested (0.001–1.0 μg/kg/injection). However, combining etonitazene (0.1–1.0 μg/kg/injection) with cocaine (0.01 and 0.03 mg/kg/injection) enhanced cocaine self-administration, and this enhancement was attenuated by naltrexone. These effects are similar to those obtained by combining non-reinforcing doses of heroin and cocaine. Antagonism of etonitazene–cocaine and heroin–cocaine self-administration by naloxonazine was short lasting and was not maintained after 24 h (when naloxonazine’s purported μ1 subtype antagonist effects are thought to predominate).

Conclusions

The results suggest that high μ agonist efficacy does not guarantee consistent drug self-administration and that the ability of μ agonists to enhance cocaine self-administration does not depend exclusively on reinforcing efficacy. Moreover, the results do not support a major role for μ1 receptor mechanisms in either etonitazene- or heroin-induced enhancement of cocaine self-administration.

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Acknowledgments

We thank Laura Teixeira and Annemarie Duggan for their expert technical assistance and Donna Reed for editorial assistance. We also acknowledge NIDA for providing a generous gift of Heroin HCl. The work was supported by United States Public Health Service Grants DA11928 and RR00168.

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Authors and Affiliations

  1. Division of Neuroscience, New England Primate Research Center, Harvard Medical School, One Pine Hill Dr., P. O. Box 9102, Southborough, MA, 01772, USA

    Cindy Achat-Mendes, Glenn R. Valdez, Donna M. Platt, James K. Rowlett & Roger D. Spealman

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  1. Cindy Achat-Mendes
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  2. Glenn R. Valdez
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  3. Donna M. Platt
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  4. James K. Rowlett
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  5. Roger D. Spealman
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Correspondence to Cindy Achat-Mendes.

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Achat-Mendes, C., Valdez, G.R., Platt, D.M. et al. Intravenous self-administration of etonitazene alone and combined with cocaine in rhesus monkeys: comparison with heroin and antagonism by naltrexone and naloxonazine. Psychopharmacology 204, 489–498 (2009). https://doi.org/10.1007/s00213-009-1480-0

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  • DOI: https://doi.org/10.1007/s00213-009-1480-0

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