Abstract
Repeated forced-swim stress (FSS) produced analgesia, immobility and potentiation of cocaine-conditioned place preference (CPP) in wild-type C57Bl/6 mice, but not in littermates lacking the kappa opioid receptor (KOR) gene. These results were surprising because kappa agonists are known to produce conditioned place aversion and to suppress cocaine-CPP when coadministered with cocaine. The possibility that disruption of the kappa system blocked the stress response by adversely affecting the hypothalamic-pituitary axis was examined by measuring plasma corticosterone levels. However, disruption of the dynorphin/kappa system by gene deletion or receptor antagonism did not reduce the FSS-induced elevation of plasma corticosterone levels. A second explanation for the difference is that kappa receptor activation caused by FSS occurred prior to cocaine conditioning rather than contemporaneously. To test this hypothesis, we measured the effects of the kappa agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) administered to mice at various intervals preceding cocaine conditioning. The results showed that the interaction between the kappa system and cocaine reinforcement depended on the timing of the drug pairing. Mice given U50,488 60 min prior to cocaine showed a robust, nor-BNI-sensitive potentiation of cocaine-CPP, whereas administration 15 min before cocaine significantly suppressed cocaine-CPP. In the absence of cocaine, U50,488 given 60 min prior to saline conditioning produced no place preference, whereas administration 15 min before saline conditioning produced significant place aversion. The results of this study suggest that kappa receptor activation induced by FSS prior to the cocaine-conditioning session may be both necessary and sufficient for potentiation of the reinforcing actions of cocaine.
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Acknowledgements
We thank Dr Uwe Hochgeschwender for generously providing the prodynorphin knockout mice. Joe Novak performed the mouse genotyping. The work was supported by USPHS Grants RO1 DA16898 and PO1-DA15916 (to CC) and RO3 Grants DA016656 and DA016415 (to JPM) from the National Institute on Drug Abuse.
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McLaughlin, J., Land, B., Li, S. et al. Prior Activation of Kappa Opioid Receptors by U50,488 Mimics Repeated Forced Swim Stress to Potentiate Cocaine Place Preference Conditioning. Neuropsychopharmacol 31, 787–794 (2006). https://doi.org/10.1038/sj.npp.1300860
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DOI: https://doi.org/10.1038/sj.npp.1300860
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