The mechanism of ethanol enhancement of α4β2-type neuronal nicotinic acetylcholine receptors in rat cortical neurons

Takashi Mori*, Kiyonobu Nishikawa, Jay Z. Yeh, Toshio Narahashi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Ethanol has been shown to modulate the activity of a variety of neurotransmitter systems. Recent electrophysiological study using a primary culture of rat cortical neurons demonstrated that ethanol at physiological concentration significantly potentiated α-bungarotoxin-insensitive (α4β2-type) neuronal nicotinic acetylcholine receptors (nnAChRs). Interestingly, ethanol potentiates α4β2-type currents above the saturated ACh response. Similar effects have been observed in muscle type nAChRs expressed in HEK cell. This phenomenon cannot be explained solely by an increase in the ACh affinity. Several hypotheses are proposed for the mechanism of this phenomenon: 1) ethanol increases channel open probability; 2) ethanol relieves an agonist-induced self-inhibition of the nicotinic receptor channel; 3) ethanol permits activation of silent receptors which are postulated to emerge to the surface of the cell membrane when they are activated; 4) ethanol increases single channel conductance. The present study was conducted in order to obtain a clue to the mechanism of ethanol enhancement of α4β2-type nnAChRs by using whole-cell patch-clamp current recording in rat cortical neurons. First, to examine the ethanol action on an agonist-induced self-inhibition of the nnAChRs, a full range of ACh concentrations were tested. Higher concentration of ACh inhibited α4β2-type currents resulting in bell-shaped doseresponse curve. Ethanol enhanced α4β2-type currents at all ACh concentrations tested, 20% increase at saturated response. The effect of ethanol on ACh bell-shaped dose-response curve showed that ACh EC50 and IC50 reduced slightly. The effect of ethanol on cytisine bell-shaped dose-response curve was similar to those on ACh dose-response curve. These results indicate ethanol does not release agonist-induced self inhibition. Second, to determine whether if ethanol can activate silent receptors, we observed the ethanol enhancement of α4β2-type currents after block of nnAChRs by chlorisondamine, an irreversible open channel blocker. The absolute enhancement of ACh-induced currents after chlorisondamine block was much smaller than that estimated from the α4β2-type currents amplitudes before chlorisondamine block. This result suggests that ethanol does not activate silent nnAChRs. Finally, simulation considering nnAChRs channel gating was performed on the ACh doseresponse data obtained in the experiments, This simulation revealed that ethanol could increase nnAChRs open probability. Recent single channel experiments on α4β2 nnAChRs expressed in HEK cell also proved increase of open probability by ethanol. In conclusion, ethanol enhancement of α4β2-type nnAChRs was not due to either relief from the agonist-induced self inhibition or activation of silent receptors.

Original languageEnglish (US)
Pages (from-to)193-194
Number of pages2
JournalAnesthesia and Resuscitation
Issue number4
StatePublished - Dec 2002

ASJC Scopus subject areas

  • Emergency Medicine
  • Anesthesiology and Pain Medicine

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