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Effect of the κ opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice

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Abstract

Rationale

While the effects of several kappa opioid receptor agonists on cocaine-induced reward have been studied, such effects of R-84760, a novel non-peptidic, potent and selective kappa opioid agonist that has been studied in humans, are not yet known.

Objective

To study the effects of R-84760 on basal levels of dopamine, cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and locomotor activity in mice.

Methods

In the first experiment, R-84760 was administered i.p. (0, 0.01, 0.05 or 0.1 mg/kg) to C57BL/6J mice. Its effect on basal dopamine levels in the caudate putamen was measured with in vivo microdialysis. In the second experiment, the effect of pretreatment with 0.1 mg/kg R-84760 on cocaine-induced increases in dopamine levels was studied. The third experiment examined the effect of R-84760 (0.1 mg/kg) on the development of cocaine-induced conditioned place preference and locomotor activity in the conditioning chamber.

Results

R-84760 decreased dopamine levels in a dose-dependent manner. The highest dose of R-84760 (0.1 mg/kg, i.p.) significantly decreased dopamine levels relative to vehicle, an effect completely blocked by pre-injection with 10 mg/kg of the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same dose of R-84760 blocked cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and attenuated cocaine-induced locomotor response.

Conclusion

These findings suggest that R-84760 decreases dopamine levels in the caudate putamen through kappa-opioid receptors. The inhibitory effect of R-84760 on striatal dopamine may contribute to its blockade of cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and the associated increases in locomotor activity.

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Acknowledgements

We thank Susan Russo for her careful reading of the manuscript. This work was supported by National Institutes of Health-National Institute on Drug Abuse Research Center Grant P60-DA05130 and National Institute on Drug Abuse Research Scientist Award K05-DA00049 to Dr. Mary Jeanne Kreek.

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Authors and Affiliations

  1. The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10021, USA

    Yong Zhang, Eduardo R. Butelman, Stefan D. Schlussman, Ann Ho & Mary Jeanne Kreek

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  1. Yong Zhang
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  2. Eduardo R. Butelman
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  3. Stefan D. Schlussman
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  4. Ann Ho
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  5. Mary Jeanne Kreek
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Correspondence to Yong Zhang.

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Zhang, Y., Butelman, E.R., Schlussman, S.D. et al. Effect of the κ opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice. Psychopharmacology 173, 146–152 (2004). https://doi.org/10.1007/s00213-003-1716-3

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  • DOI: https://doi.org/10.1007/s00213-003-1716-3

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