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, 33 (3), 643-52

Pharmacological Evidence for a Motivational Role of Kappa-Opioid Systems in Ethanol Dependence

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Pharmacological Evidence for a Motivational Role of Kappa-Opioid Systems in Ethanol Dependence

Brendan M Walker et al. Neuropsychopharmacology.

Abstract

The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (kappa)-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 kappa-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 mu-opioid receptor, and nalmefene is primarily selective for the mu- and kappa-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the mu-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that kappa-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/kappa-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats.

Conflict of interest statement

DISCLOSURES

Neither of the authors has any conflicts of interest related or unrelated to this manuscript.

Figures

Figure 1
Figure 1
Left panel: Mean (± SEM) responses for ethanol and water prior to dependence induction for the ethanol vapor- and air-exposed groups. Right panel: Mean (± SEM) responses for ethanol and water at a time point corresponding to 6 h into withdrawal (ie, acute withdrawal) following dependence induction. The vapor-exposed animals display escalated responding compared to the air-exposed controls.
Figure 2
Figure 2
Mean (+ SEM) responses for ethanol following nalmefene (0.0–0.1 mg/kg) and naltrexone (0.0–1.0 mg/kg) administration in nondependent and ethanol-dependent animals during acute withdrawal. Both nalmefene and naltrexone-induced dose-dependent decreases in ethanol self-administration (*p < 0.05 and **p < 0.01 compared to vapor-exposed vehicle dose; #p < 0.05, and ##p < 0.01 compared to air-exposed vehicle dose).
Figure 3
Figure 3
Mean (+ SEM) responses for water following nalmefene (0.0–0.1 mg/kg) and naltrexone (0.0–1.0 mg/kg) administration in nondependent and ethanol-dependent animals during acute withdrawal.
Figure 4
Figure 4
Mean (± SEM) responses for ethanol in nondependent and ethanol-dependent animals following 0.1 mg/kg nalmefene or naltrexone. Nalmefene attenuated responding for ethanol significantly more than naltrexone (*p < 0.05) in ethanol-dependent animals.
Figure 5
Figure 5
Mean (+ SEM) responses for ethanol in nondependent and ethanol-dependent animals during acute withdrawal following nor-BNI treatment before self-administration sessions. Nor-BNI selectively attenuated ethanol self-administration in dependent animals (**p < 0.01, ***p < 0.001 compared to vapor-exposed vehicle dose).
Figure 6
Figure 6
Mean (+ SEM) responses for water in nondependent and ethanol-dependent animals during acute withdrawal following nor-BNI treatment before self-administration sessions.

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