title: κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.
abstract: Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone.
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Mail Code: 644820, Pullman, WA 99164-4820, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Nealey
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Smith
authors.forename: Seth M
authors.initials: SM
authors.lastname: Davis
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Smith
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Walker
mesh_terms: D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D057967:Infusions, Intraventricular; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology*; D012646:Self Administration
chemical_list: D017473:Receptors, Opioid, kappa; D000431:Ethanol; D009271:Naltrexone; C038981:nalmefene