Characterization of metabotropic glutamate receptor-mediated facilitation of N-methyl-D-aspartate depolarization of neocortical neurones

1 Facilitation of the N-methyl-D-aspartate (NMDA) receptor-mediated depolarization of cortical neurones induced by metabotropic glutamate receptor (mGluR) agonists in the presence of tetrodotoxin has been examined by use of grease-gap recording. 2 Quisqualate (1-2 mu M) and 10 to 100 mu M 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) facilitated the NMDA-, but not the kainate-induced depolarization with an EC(50) of 16 mu M for 1S,3R-ACPD. The facilitation induced by quisqualate was reduced, but not blocked, by 4 mu M 6-cyano-7-nitroquinoxaline-2,3-dione. 3 D,L-2-Amino-3-phosphonopropionic acid and D,L-2-amino-4-phosphonobutyric acid antagonized the 1S,3R-ACPD facilitation in a non-competitive manner with IC50 values of 0.24 mu M and 4.4 mu M respectively. 4 Homologous desensitization of the 1S,3R-ACPD induced facilitation was not observed. The facilitation was not altered by 10 nM staurosporine or 3 mu M phorbol diacetate. 5 Substitution of 20 mu M 8-bromo-cyclic adenosine monophosphate, 20 mu M 8-bromo-cyclic guanosine monophosphate, or 10 mu M arachidonic acid for 1S,3R-ACPD did not induce facilitation of the NMDA response. However, the 1S,3R-ACPD facilitation was potentiated by 10 mM myo-inositol and exhibited heterologous desensitization following exposure to 100 mu M 5-hydroxytryptamine. 6 The 1S,3R-ACPD-induced facilitation persisted in both 10 mu M nifedipine and nominally Ca2+-free medium and was only gradually eliminated following addition of 100 mu M bis-(-o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid in Ca2+-free medium. Facilitation of the NMDA response induced by carbachol, but not phenylephrine, was also observed in nominally Ca2+-free medium. Perfusing 50 mu M bis-(-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid aminoethoxy eliminated the 1S,3 R-ACPD facilitation. 7 These experiments have shown that mGluR agonists selectively facilitate the NMDA depolarization of cortical wedges, most likely by activating one or more mGluR subtypes that couple to phospholipase C. We conclude the facilitation results from a Ca2+-sensitive mechanism dependent on activation of phospholipase C and release of internal Ca2+. The facilitation is not contingent on activation of protein kinase C or entry of Ca2+ through nifedipine-sensitive Ca2+ channels.