Developmental decrease in ethanol inhibition of N-methyl-D-aspartate receptors in rat neocortical neurons: relation to the actions of ifenprodil

Lovinger, D.M.

Journal of Pharmacology and Experimental Therapeutics 274(1): 164-172


ISSN/ISBN: 0022-3565
PMID: 7616394
Accession: 008456619

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Inhibition of N-methyl-D-aspartate (NMDA) receptor function by ethanol (EtOH) and interactions between EtOH and the noncompetitive NMDA receptor antagonist ifenprodil were examined in neocortical neurons from rat and human embryonic kidney (HEK) 293 cells expressing recombinant NMDA receptors. Ethanol inhibited receptor function at concentrations in the 10 to 100 mM range in cortical neurons. EtOH inhibition of NMDA receptor function decreased as a function of time in culture over a 4-wk period. No difference in EtOH inhibition of AMPA/kainate receptor function was observed in neurons from 2- to 4-wk-old cultures. The time course of decreased EtOH inhibition paralleled a developmental decrease in inhibition by the noncompetitive NMDA receptor antagonist ifenprodil in these cortical neurons. Inhibition by EtOH was decreased in magnitude in the presence of 10 mu-M ifenprodil in 2- to 3-wk-old cortical neurons, but not in 1-wk-old neurons. Ifenprodil inhibited the function of recombinant NMDA receptors expressed in HEK 293 cells. Consistent with earlier reports, ifenprodil selectively inhibited responses mediated by recombinant receptors containing the NMDAR2B subunit at concentrations up to 10 mu-M. EtOH also inhibited the function of recombinant NMDA receptors expressed in HEK 293 cells. The potency of EtOH for inhibiting responses differed slightly among receptors containing different R2 subunits, especially at low EtOH concentrations. Finally, ifenprodil did not alter the effect of EtOH on recombinant R2A or 2B-containing NMDA receptors. These findings indicate 1) that EtOH sensitivity of receptors in cortical neurons changes during early postnatal development; 2) that ifenprodil-sensitive NMDA receptors on cortical neurons are especially sensitive to the effects of EtOH and 3) that EtOH and ifenprodil do not interact at a single site on the NMDA receptor/channel complex. The presence of the NMDAR2B subunit appears to be one characteristic of NMDA receptor subtypes with high EtOH sensitivity in cortical neurons. However, the presence of this subunit is not the sole determinant of EtOH sensitivity.