Alpha6-containing nicotinic acetylcholine receptor is a highly sensitive target of alcohol.

Neuropharmacology 2019 May 01

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Alcohol use disorder (AUD) is a serious public health problem that results in tremendous social, legal and medical costs to society. Unlike other addictive drugs, there is no specific molecular target for ethanol (EtOH). Here, we report a novel molecular target that mediates EtOH effects at concentrations below those that cause legally-defined inebriation. Using patch-clamp recording of human α6*-nicotinic acetylcholine receptor (α6*-nAChR) function when heterologously expressed in SH-EP1 human epithelial cells, we found that 0.1-5 mM EtOH significantly enhances α6*-nAChR-mediated currents with effects that are dependent on both EtOH and nicotine concentrations. EtOH exposure increased both whole-cell current rising slope and decay constants. This EtOH modulation was selective for α6*-nAChRs since it did not affect α3β4-, α4β2-, or α7-nAChRs. In addition, 5 mM EtOH also increased the frequency and amplitude of dopaminergic neuron transients in mouse brain nucleus accumbens slices, that were blocked by the α6*-nAChR antagonist, α-conotoxin MII, suggesting a role for native α6*-nAChRs in low-dose EtOH effects. Collectively, our data suggest that α6*-nAChRs are sensitive targets mediating low-dose EtOH effects through a positive allosteric mechanism, which provides new insight into mechanisms involved in pharmacologically-relevant alcohol effects contributing to AUD. Copyright © 2019. Published by Elsevier Ltd.

Citation

Fenfei Gao, Dejie Chen, Xiaokuang Ma, Sterling Sudweeks, Jordan T Yorgason, Ming Gao, Dharshaun Turner, Jason Brek Eaton, J Michael McIntosh, Ronald J Lukas, Paul Whiteaker, Yongchang Chang, Scott C Steffensen, Jie Wu. Alpha6-containing nicotinic acetylcholine receptor is a highly sensitive target of alcohol. Neuropharmacology. 2019 May 01;149:45-54