UFR2709, a Nicotinic Acetylcholine Receptor Antagonist, Decreases Ethanol Intake in Alcohol-Preferring Rats.

Gabriel Quiroz,Ramón Sotomayor-Zárate,Franco Vizcarra,Diego Lagos,Patricio Iturriaga-Vásquez,Isabel Bermudez,Juan Pablo González-Gutierrez,María Elena Quintanilla,Miguel Reyes-Parada,Mario Rivera-Meza,Felipe Moraga

doi:10.3389/fphar.2019.01429

Abstract

Brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric acetylcholine-gated cation channels, have been suggested as molecular targets for the treatment of alcohol abuse and dependence. Here, we examined the effect of the competitive nAChR antagonist UFR2709 on the alcohol consumption of high-alcohol-drinking UChB rats. UChB rats were given free access to ethanol for 24-h periods in a two-bottle free choice paradigm and their ethanol and water intake were measured. The animals were i.p. injected daily for 17 days with a 10, 5, 2.5, or 1 mg/kg dose of UFR2709. Potential confounding motor effects of UFR2709 were assessed by examining the locomotor activity of animals administered the highest dose of UR2709 tested (10 mg/kg i.p.). UFR2709 reduced ethanol consumption and ethanol preference and increased water consumption in a dose-dependent manner. The most effective dose of UFR2709 was 2.5 mg/kg, which induced a 56% reduction in alcohol consumption. Administration of UFR2709 did not affect the weight or locomotor activity of the rats, suggesting that its effects on alcohol consumption and preference were mediated by specific nAChRs.

Highlights

Alcohol is the most commonly abused legal substance and alcoholism is a serious public health problem worldwide (WHO, 2014)
Ethanol intake appears to involve a variety of nicotinic acetylcholine receptors (nAChRs) subtypes (Joslyn et al, 2008; Saccone et al, 2009; Taslim and Saeed Dar, 2011). α7 (Kamens et al, 2010a) and α3β4 nAChRs (Chatterjee et al, 2011; Miller et al, 2019) have both been implicated in ethanol intake, and receptors containing the α5 nAChR subunit are thought to be associated with the sedative effects of ethanol (Santos et al, 2013)
Ethanol activates the mesolimbic-DA system, inducing the release of DA in the nucleus accumbens from projections that arise in the ventral tegmental area (VTA) (Gessa et al, 1985; Di Chiara and Imperato, 1988)

Summary

Introduction

Alcohol is the most commonly abused legal substance and alcoholism is a serious public health problem worldwide (WHO, 2014). VTA dopaminergic neurons primarily express the α4β2 nAChR subtype, and express nAChRs exhibiting combinations of α5 and α6 subunits (Klink et al, 2001; Azam et al, 2002) These nAChRs are activated by cholinergic inputs from the laterodorsal tegmental and pedunculopontine tegmental nuclei (Oakman et al, 1995; Jerlhag et al, 2012; Xiao et al, 2016). Voluntary ethanol consumption increases ACh levels in the VTA and promotes DA overflow in the nucleus accumbens in rats (Larsson et al, 2005) This establishes a cholinergic-dopaminergic reward axis (Xiao et al, 2016), which is affected by ethanol (Engel and Jerlhag, 2014)

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Results

Discussion

Conclusion