Abstract
The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (κ)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective κ-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the μ-opioid receptor, and nalmefene is primarily selective for the μ- and κ-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the μ-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that κ-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/κ-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats.
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Acknowledgements
Support for this Research was provided by National Institute on Alcohol Abuse and Alcoholism grants awarded to GFK (AA012602) and a National Research Service Award awarded to BMW (AA014723). We thank Dr. Eric Zorrilla for his statistical advice, Maury Cole, Mallinckrodt Inc., and The Pearson Center for Alcoholism and Addiction Research for their assistance with this project and Mike Arends for editorial assistance.
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Walker, B., Koob, G. Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence. Neuropsychopharmacol 33, 643–652 (2008). https://doi.org/10.1038/sj.npp.1301438
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DOI: https://doi.org/10.1038/sj.npp.1301438
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