Alcohol and Alcoholism Advance Access published online on October 29, 2008
Alcohol and Alcoholism, doi:10.1093/alcalc/agn085
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The Novel µ-Opioid Receptor Antagonist, [N-Allyl-Dmt1]Endomorphin-2, Attenuates the Enhancement of GABAergic Neurotransmission by Ethanol
1 Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA
2 Neurobiology Research Laboratory, VA Medical Center, NC 27705, USA
3 Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences and The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
4 Medicinal Chemistry Group, Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
5 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
* Corresponding author: Department of Psychiatry, Duke University Medical Center, Room 24, Building 16, VA Medical Center, 508 Fulton Street, Durham, NC 27705, USA. Tel: +1-919-286-6810; Fax: +1-919-286-4662; E-mail: HSS{at}duke.edu
Received 15 January 2008; first review notified 24 June 2008; in revised form 19 August 2008; accepted 2 October 2008
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Abstract |
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Aims: We investigated the effects of [N-allyl-Dmt1]endomorphin-2 (TL-319), a novel and highly potent µ-opioid receptor antagonist, on ethanol (EtOH)-induced enhancement of GABAA receptor-mediated synaptic activity in the hippocampus.Methods: Evoked and spontaneous inhibitory postsynaptic currents (eIPSCs and sIPSCs) were isolated from CA1 pyramidal cells from brain slices of male rats using whole-cell patch-clamp techniques.Results: TL-319 had no effect on the baseline amplitude of eIPSCs or the frequency of sIPSCs. However, it induced a dose-dependent suppression of an ethanol-induced increase of sIPSC frequency with full reversal at concentrations of 500 nM and higher. The non-specific competitive opioid receptor antagonist naltrexone also suppressed EtOH-induced increases in sIPSC frequency but only at a concentration of 60 µM.Conclusion: These data indicate that blockade of µ-opioid receptors by low concentrations of [N-allyl-Dmt1]endomorphin-2 can reverse ethanol-induced increases in GABAergic neurotransmission and possibly alter its anxiolytic or sedative effects. This suggests the possibility that high potency opioid antagonists may emerge as possible candidate compounds for the treatment of ethanol addiction.