1 The metabotropic glutamate receptor (mGluR) agonist trans-(+)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) (10 ± 100 mM) depolarized isolated frog spinal cord motoneurones, a process sensitive to kynurenate (1.0 mM) and tetrodotoxin (TTX) (0.783 mM). 2 In the presence of NMDA open channel blockers [Mg 2+ ; (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine hydrogen maleate (MK801); 3,5-dimethyl-1-adamantanamine hydrochloride (memantine)] and TTX, trans-ACPD signi®cantly potentiated NMDA-induced motoneurone depolarizations, but not a-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA)-or kainate-induced depolarizations. 3 NMDA potentiation was blocked by (RS)-a-methyl-4-carboxyphenylglycine (MCPG) (240 mM), but not by a-methyl-(2S,3S,4S)-a-(carboxycyclopropyl)-glycine (MCCG) (290 mM) or by a-methyl-(S)-2-amino-4-phosphonobutyrate (L-MAP4) (250 mM), and was mimicked by 3,5-dihydroxyphenylglycine (DHPG) (30 mM), but not by L(+)-2-amino-4-phosphonobutyrate (L-AP4) (100 mM). Therefore, trans-ACPD's facilitatory e ects appear to involve group I mGluRs. 4 Potentiation was prevented by the G-protein decoupling agent pertussis toxin (3 ± 6 ng ml 71 , 36 h preincubation). The protein kinase C inhibitors staurosporine (2.0 mM) and N-(2-aminoethyl)-5-isoquinolinesulphonamide HCl (H9) (77 mM) did not signi®cantly reduce enhanced NMDA responses. Protein kinase C activation with phorbol-12-myristate 13-acetate (5.0 mM) had no e ect. 5 Intracellular Ca 2+ depletion with thapsigargin (0.1 mM) (which inhibits Ca 2+ /ATPase), 1,2-bis(Oaminophenoxy)ethane-N,N,N',N'-tetracetic acid acetyl methyl ester (BAPTA-AM) (50 mM) (which bu ers elevations of [Ca 2+ ] i ), and bathing spinal cords in nominally Ca 2+ -free medium all reduced trans-ACPD's e ects. 6 The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7) (100 mM) and chlorpromazine (100 mM) diminished the potentiation. 7 In summary, group I mGluRs selectively facilitate NMDA-depolarization of frog motoneurones via a G-protein, a rise in [Ca 2+ ] i from the presumed generation of phosphoinositides, binding of Ca 2+ to calmodulin, and lessening of the Mg 2+ -produced channel block of the NMDA receptor.
