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Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates

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Abstract

Rationale

Dopamine D1 receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D1 receptor drugs produce these similar effects on cocaine seeking are unknown.

Objectives

This study investigated how D1 receptor agonists and antagonists alter the shape and position of the dose–response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus.

Methods

Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D1 receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3–4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking.

Results

Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D1 receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose–response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually.

Conclusions

These findings suggest that D1 receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D1 receptors.

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Acknowledgements

We thank Susanna Fryer, Allison Martino, Carl Hakansson, and Donna Reed for technical assistance. This research was supported by National Institutes of Health grants DA11054, DA00499, and RR00168 and by an unrestricted grant from the Schering Plough Research Institute. Compound SKF 83959 was provided by Research Biochemicals International as part of the Chemical Synthesis Program of the National Institute of Mental Health, Contract NO1MH30003.

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Authors and Affiliations

  1. SRI International, Center for Health Sciences, 333 Ravenswood Ave, Menlo Park, CA 94025, USA

    Taline V. Khroyan

  2. New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA

    Taline V. Khroyan, Donna M. Platt, James K. Rowlett & Roger D. Spealman

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  1. Taline V. Khroyan
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  2. Donna M. Platt
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  3. James K. Rowlett
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  4. Roger D. Spealman
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Correspondence to Taline V. Khroyan.

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Khroyan, T.V., Platt, D.M., Rowlett, J.K. et al. Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates. Psychopharmacology 168, 124–131 (2003). https://doi.org/10.1007/s00213-002-1365-y

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  • DOI: https://doi.org/10.1007/s00213-002-1365-y

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