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

• Published in: Neuropharmacology Vol. 149; pp. 45 - 54
• Main Authors: Gao, Fenfei, Chen, Dejie, Ma, Xiaokuang, Sudweeks, Sterling, Yorgason, Jordan T., Gao, Ming, Turner, Dharshaun, Eaton, Jason Brek, McIntosh, J. Michael, Lukas, Ronald J., Whiteaker, Paul, Chang, Yongchang, Steffensen, Scott C., Wu, Jie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2019
• Subjects: Alcohol; Alcoholism; Alpha 6 subunit; Animals; Cell Culture Techniques; Cell Line, Tumor; Conotoxins - pharmacology; Dopamine; Dopaminergic Neurons - physiology; Ethanol; Ethanol - pharmacology; Humans; Mice; Mice, Inbred C57BL; Neurons - drug effects; Neurons - physiology; Nicotine - pharmacology; Nicotinic acetylcholine receptor; Nicotinic Antagonists - pharmacology; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiology; Patch-clamp; Patch-Clamp Techniques; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - physiology; SH-EP1 cells; Synaptic Transmission - drug effects; Alcohol; Ethanol; Patch-clamp; SH-EP1 cells; Nicotinic acetylcholine receptor; Alpha 6 subunit
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.01.021

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.
•A novel cell line expressing human nicotinic acetylcholine receptors containing (α6*-nAChR) is used.•Patch-clamp recording shows potentiation by low dose ethanol (0.1–5 mM) of α6*-, but not α3β4-, α4β2- or α7-nAChR function.•These effects are ethanol and nicotine concentration-dependent, consistent with positive allosteric action of ethanol.•5 mM ethanol increases dopamine neuron transient frequency and amplitude in mouse brain nucleus accumbens slices.•α-conotoxin MII sensitivity indicates that native α6*-nAChR mediate low dose ethanol effects on dopamine neuronal function.