Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor.
Phosphorylation of C-termini of receptor subunits is thought to play a significant role in modulation of N-methyl-D-aspartic acid (NMDA) receptor function. To investigate whether the C-terminus of the NR2A subunit is involved in determining the sensitivity of NMDA receptors to ethanol we compared the effects of ethanol in vitro on NMDA-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 and dentate gyrus (DG) of adult male NR2A(DeltaC/DeltaC) mice lacking the C-terminus of NR2A subunit and in their parental strain C57Bl/6. We also tested the in vivo effects of a hypnotic dose of ethanol in C57Bl/6 and NR2A(DeltaC/DeltaC) mice and their F2 offspring. Ifenprodil (10 microM) was used to distinguish between the NR2A and NR2B components of NMDA fEPSPs. Ethanol (100 mM) in the presence of ifenprodil inhibited the CA1 NR2A-mediated component of NMDA fEPSPs two times more in NR2A(DeltaC/DeltaC) than in C57Bl/6. Ethanol inhibition of the CA1 NR2B-mediated component was five to seven times lower in NR2A(DeltaC/DeltaC) than in C57Bl/6. In the DG ethanol had similar effects in the two strains. In vivo administration of ethanol (4 g/kg) induced sedation of similar duration in both strains of mice. A second administration of ethanol 7 days after the initial injection revealed an increased ethanol sensitivity of NR2A(DeltaC/DeltaC) and F2(DeltaC/DeltaC) mice including a shortened time to loss of righting reflex and an increased sleep time. The sensitization of NR2A(DeltaC/DeltaC) mice to alcohol was not accompanied by an altered ethanol sensitivity of NMDA fEPSPs recorded in vitro. Our data are consistent with the inhibitory action of ethanol on NMDA receptors being mediated by a site other than the intracellular C-terminus of the NR2A subunit. The altered sensitivities to ethanol of both NR2A- and NR2B-mediated responses in the CA1 of NR2A(DeltaC/DeltaC) imply that NR2A- and NR2B subunit-containing NMDA receptors may be linked by a common target of ethanol.
Gordey
M
M
Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Mekmanee
L
L
Mody
I
I
D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics* / Q000502:physiology
D006993:Hypnotics and Sedatives; C120997:NR2A NMDA receptor; D010446:Peptide Fragments; D010880:Piperidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C010739:ifenprodil