Inhibition of rat recombinant GluN1/GluN2A and GluN1/GluN2B NMDA receptors by ethanol at concentrations based on the US/UK drink-drive limit.
Many studies examine the actions of ethanol on N-methyl-D-aspartate (NMDA) receptors using concentrations that are highly toxic (>or=100 mM). This study re-assesses the actions of ethanol at concentrations based around the US/UK 'drink-drive' limit (17 mM). Using two-electrode voltage-clamp recordings we examined the actions of ethanol on recombinant GluN1/GluN2A and GluN1/GluN2B NMDA receptors expressed in Xenopus laevis oocytes. We also investigated its actions on NMDA receptors containing GluN2A subunits with truncated or deleted carboxy terminal domains. Ethanol inhibition was voltage-independent and for GluN1/GluN2A NMDA receptors mean inhibition (20 mM at -60 mV) was 9.5+/-0.8% (n=33) while corresponding values for GluN1/GluN2B NMDA receptors were 6.5+/-0.8% (n=21). EC(50) values for glutamate at GluN1/GluN2A and glutamate and glycine at GluN1/GluN2B NMDA receptors were unaffected by the presence of ethanol. We did however observe a small increase in glycine potency, in the presence of ethanol, at GluN1/GluN2A NMDA receptors. Neither voltage-dependent Mg(2+) block nor memantine block was affected by ethanol. Reduced ethanol inhibition was observed however at NMDA receptors containing GluN2A subunits with mutated carboxy terminal domains. We conclude that the levels of inhibition seen with ethanol concentrations near to the US/UK drink-driving limit are very modest and even at higher (intoxicating) concentrations do not alter characteristic NMDA receptor properties.
Otton
Hannah J
HJ
Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Janssen
Ariane
A
O'Leary
Timothy
T
Chen
Philip E
PE
Wyllie
David J A
DJ
D000428:Alcohol Drinking; D000818:Animals; D001334:Automobile Driving / Q000331:legislation & jurisprudence*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006113:United Kingdom; D014481:United States
C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D000431:Ethanol