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

ABSTRACT: 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 ?6*-nicotinic acetylcholine receptor (?6*-nAChR) function when heterologously expressed in SH-EP1 human epithelial cells, we found that 0.1-5 mM EtOH significantly enhances ?6*-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 ?6*-nAChRs since it did not affect ?3?4-, ?4?2-, or ?7-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 ?6*-nAChR antagonist, ?-conotoxin MII, suggesting a role for native ?6*-nAChRs in low-dose EtOH effects. Collectively, our data suggest that ?6*-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.

SUBMITTER: Gao F

PROVIDER: S-EPMC7323585 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Gao Fenfei F Chen Dejie D Ma Xiaokuang X Sudweeks Sterling S Yorgason Jordan T JT Gao Ming M Turner Dharshaun D Eaton Jason Brek JB McIntosh J Michael JM Lukas Ronald J RJ Whiteaker Paul P Chang Yongchang Y Steffensen Scott C SC Wu Jie J

Neuropharmacology 20190130

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 ...[more]

PMID: 30710570

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Project description:Midbrain dopamine (DA) neurons are considered a critical substrate for the reinforcing and sensitizing effects of nicotine and tobacco dependence. While the role of the α4 and β2 subunit containing nicotinic acetylcholine receptors (α4β2∗nAChRs) in mediating nicotine effects on DA release and DA neuron activity has been widely explored, less information is available on their role in the morphological adaptation of the DA system to nicotine, eventually leading to dysfunctional behaviors observed in nicotine dependence. In particular, no information is available on the role of α6∗nAChRs in nicotine-induced structural plasticity in rodents and no direct evidence exists regarding the occurrence of structural plasticity in human DA neurons exposed to nicotine. To approach this problem, we used two parallel in vitro systems, mouse primary DA neuron cultures from E12.5 embryos and human DA neurons differentiated from induced pluripotent stem cells (iPSCs) of healthy donors, identified using TH+ immunoreactivity. In both systems, nicotine 1-10 μM produced a dose-dependent increase of maximal dendrite length, number of primary dendrites, and soma size when measured after 3 days in culture. These effects were blocked by pretreatments with the α6∗nAChR antagonists α-conotoxin MII and α-conotoxin PIA, as well as by the α4β2nAChR antagonist dihydro-β-erythroidine (DHβE) in both mouse and human DA neurons. Nicotine was also ineffective when the primary DA neurons were obtained from null mutant mice for either the α6 subunit or both the α4 and α6 subunits of nAChR. When pregnant mice were exposed to nicotine from gestational day 15, structural plasticity was also observed in the midbrain DA neurons of postnatal day 1 offspring only in wild-type mice and not in both null mutant mice. This study confirmed the critical role of α4α6∗nAChRs in mediating nicotine-induced structural plasticity in both mouse and human DA neurons, supporting the translational relevance of neurons differentiated from human iPSCs for pharmacological studies.

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

Publications

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

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