Journal article
κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
Neuropharmacology, Vol.61(1), pp.35-42
2011
Handle:
https://hdl.handle.net/2376/116472
PMCID: PMC3955175
PMID: 21338616
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 was 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 than those that target μ- and δ-opioid receptor mechanisms alone.
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Details
- Title
- κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
- Creators
- Kathryn A Nealey - Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WAAlexander W Smith - Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WASeth M Davis - Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WADaniel G Smith - Neuroscience Department, Lundbeck Research USA, Inc., Paramus, NJBrendan M Walker - Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, WA
- Publication Details
- Neuropharmacology, Vol.61(1), pp.35-42
- Academic Unit
- Integrative Physiology and Neuroscience, Department of
- Identifiers
- 99900547311301842
- Language
- English
- Resource Type
- Journal article