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Effect of the endogenous κ opioid agonist dynorphin A(1–17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice

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Abstract

Rationale

Effects of synthetic kappa opioid receptor agonists on cocaine-induced reward have been studied extensively in rats but relatively few studies have used the endogenous kappa agonist dynorphin A(1–17).

Objectives

Three studies were conducted to examine the effect of the natural sequence dynorphin on cocaine-induced increases in dopamine, on the formation of conditioned place preference and on increases in locomotor activity in C57BL/6 J mice.

Methods

After implantation of guide cannulae into the caudate putamen, mice were allowed 4–5 days to recover from surgery. In the first study, dynorphin A (0, 1, 2, 4.4 nmol) was infused into the caudate putamen and dopamine levels were measured by in vivo microdialysis in that brain region. Then, the effect of dynorphin A (4.4 nmol) on increases in dopamine levels induced by 15 mg/kg cocaine i.p. was also measured with in vivo microdialysis. The third experiment examined the effect of dynorphin A (4.4 nmol) on conditioned place preference and locomotion induced by 15 mg/kg cocaine.

Results

Dynorphin A significantly decreased basal dopamine levels in a dose-dependent manner by more than 60% at the highest dose, and this effect was completely blocked by pre-injection of the kappa-opioid receptor antagonist nor-BNI (10 mg/kg). The highest dose of dynorphin (4.4 nmol) blocked increases in dopamine levels, the formation of conditioned place preference and attenuated locomotion induced by 15 mg/kg cocaine.

Conclusion

The blockade of the cocaine-induced rise in striatal dopamine may contribute to both dynorphin’s ability to prevent the development of cocaine-induced conditioned place preference and to attenuate the increase 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 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 endogenous κ opioid agonist dynorphin A(1–17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice. Psychopharmacology 172, 422–429 (2004). https://doi.org/10.1007/s00213-003-1688-3

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