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Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

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Abstract

Introduction

Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug.

Results and discussion

Stress-induced reinstatement did not occur for mice pretreated with the kappa opioid receptor antagonist norbinaltorphimine (10 mg/kg) and did not occur in mice lacking either kappa opioid receptors (KOR −/−) or prodynorphin (Dyn −/−). In contrast, the initial cocaine conditioning and extinction rates were not significantly affected by disruption of the kappa opioid system. Cocaine-injection also reinstated conditioned place preference in extinguished mice; however, cocaine-primed reinstatement was not blocked by kappa opioid system disruption.

Conclusion

The results suggest that stress-induced drug craving in mice may require activation of the dynorphin/kappa opioid system.

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Abbreviations

norBNI:

norbinaltorphimine

CPP:

conditioned place preference

HSD:

Tukey honestly significant difference

KOR:

kappa opioid peptide receptor

Dyn−/−:

prodynorphin gene knockout mice

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Acknowledgements

We thank Dr. Ute Hochgeschwender for the prodynorphin knockout mice (Dyn −/−) and Dr. John Pintar for the kappa opioid receptor (KOP-r) knockout mice (KOR−/−). William Giardino helped with the behavioral assays. We also thank Dan Messinger for performing the mouse genotyping and managing the mouse-breeding colony. This work was supported by USPHS grants RO1 DA16898, KO5 DA20570 (CC), and T32 DA07278 (VR) from the National Institute on Drug Abuse.

Disclosure/Conflict of interest statement

The authors have no conflicts of interest to declare.

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  1. Department of Pharmacology, University of Washington, 1959 NE Pacific St., Seattle, WA, 98185-7280, USA

    Van A. Redila & Charles Chavkin

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  1. Van A. Redila
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  2. Charles Chavkin
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Correspondence to Charles Chavkin.

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Redila, V.A., Chavkin, C. Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology 200, 59–70 (2008). https://doi.org/10.1007/s00213-008-1122-y

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