MT-7716, a novel selective nonpeptidergic NOP receptor agonist, effectively blocks ethanol-induced increase in GABAergic transmission in the rat central amygdala.

Marsida Kallupi,George Luu,Marisa Roberto,Koji Teshima,Roberto Ciccocioppo,Christopher S Oleata

doi:10.3389/fnint.2014.00018

Abstract

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. A large body of evidence shows that Nociceptin/Orphanin FQ (N/OFQ) regulates ethanol intake and anxiety-like behavior. In the rat, ethanol significantly augments CeA GABA release, whereas N/OFQ diminishes it. Using electrophysiological techniques in an in vitro slice preparation, in this study we investigated the effects of a nonpeptidergic NOP receptor agonist, MT-7716 [(R)-2-3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl-N-methylacetamide hydrochloride hydrate], and its interaction with ethanol on GABAergic transmission in CeA slices of naïve rats. We found that MT-7716 dose-dependently (100–1000 nM) diminished evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) and increased paired-pulse facilitation (PPF) ratio of these evoked IPSPs, suggesting a presynaptic site of action of the MT-7716 by decreasing GABA release at CeA synapses. The presynaptic action of MT-7716 was also supported by the significant decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) induced by the nociceptin receptor (NOP) agonist. Interestingly, MT-7716 prevented the ethanol-induced augmentation of evoked IPSPs. A putative selective NOP antagonist, [Nphe1]Nociceptin(1–13)NH2, totally prevented the MT-7716-induced inhibition of IPSP amplitudes indicating that MT-7716 exerts its effect through NOPs. These data provide support for an interaction between the nociceptin and GABAergic systems in the CeA and for the anti-alcohol properties of the NOP activation. The development of a synthetic nonpeptidergic NOP receptor agonist such as MT-7716 may represent a useful therapeutic target for alcoholism.

Highlights

Alcoholism is a chronically relapsing disorder characterized by compulsive drug- seeking and taking (Koob and Le Moal, 1997)
MT-7716 DECREASED SPONTANEOUS MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS IN CENTRAL AMYGDALA (CeA) To further characterize the decreased GABA release induced by MT-7716, we examined spontaneous miniature inhibitory postsynaptic currents (mIPSCs) using whole-cell recordings in the presence of 1 μM TTX to eliminate action potential-dependent release of neurotransmitter
Previous studies have shown that Nociceptin/Orphanin FQ (N/OFQ) prevents and totally reverses both the acute alcohol- and CRF-induced increases in evoked inhibitory postsynaptic currents (IPSCs) amplitudes and mIPSC frequencies opposing ethanol and CRF effects on GABA release at presynaptic site (Roberto and Siggins, 2006; Cruz et al, 2012; Ciccocioppo et al, 2014)

Summary

Introduction

Alcoholism is a chronically relapsing disorder characterized by compulsive drug- seeking and taking (Koob and Le Moal, 1997). It is one of the most prevalent health problems worldwide; there are very few medications available for treating it. N/OFQ and other NOP agonists have shown an anxiolytic-like profile in animal studies (Jenck et al, 1997, 2000). It decreases alcohol drinking, and prevents relapse-like behavior in rats (Ciccocioppo et al, 2000, 2002b, 2004, 2007; Kuzmin et al, 2007; Ubaldi et al, 2013)

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Results

Conclusion