title: Subunit-specific modulation of [(3)H]MK-801 binding to NMDA receptors mediated by dopamine receptor ligands in rodent brain.
abstract: Dopamine D1 receptor (D1R) ligands may directly interact with the NMDA receptor (NMDAR), but detailed knowledge about this effect is lacking. Here we identify D1R ligands that directly modulate NMDARs and examine the contributions of NR2A and NR2B subunits to these interactions. Binding of the open channel blocker [(3)H]MK-801 in membrane preparations from rat- and mouse brain was used as a biochemical measure of the functional state of the NMDAR channel. We show that both D1R agonist A-68930 and dopamine receptor D2 antagonist haloperidol can decrease [(3)H]MK-801 binding with increased potency in membranes from the NR2A(-/-) mice (i.e. in membranes containing NR2B only), as compared to the inhibition obtained in wild-type membranes. Further, a wide range of D1R agonists such as A-68930, SKF-83959, SKF-83822, SKF-38393 and dihydrexidine were able to decrease [(3)H]MK-801 binding, all showing half maximal inhibitory concentrations ~20 μM, and with significant effects occurring at or above 1 μM. With membranes from D1R(-/-) mice, we demonstrate that these effects occurred through a D1R-independent mechanism. Our results demonstrate that dopamine receptor ligands can selectively influence NR2B containing NMDARs, and we characterize direct inhibitory NMDAR effects by different D1R ligands.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Science, University of Oslo, N-0316 Blindern, Oslo, Norway. m.b.wigestrand@medisin.uio.no
authors.forename: Mattis B
authors.initials: MB
authors.lastname: Wigestrand
authors.forename: Frode
authors.initials: F
authors.lastname: Fonnum
authors.forename: S
authors.initials: S
authors.lastname: Ivar Walaas
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D051381:Rats; D011921:Rats, Inbred WKY; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001552:Benzazepines; D016291:Dizocilpine Maleate; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C534628:SCH 23390