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Br J Pharmacol. 1997 Mar;120(6):1007-14.

Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones.

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Clinica Neurologica, Dip. Sanità, Università di Roma or Vergata, Rome, Italy.


1. The interactions between N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) were investigated in striatal slices, by utilizing intracellular recordings, both in current- and voltage-clamp mode. 2. Bath-application (50 microM) or focal application of NMDA induced a transient membrane depolarization, while in the voltage-clamp mode, NMDA (50 microM) caused a transient inward current. Following bath-application of the non-selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 10 microM), NMDA responses were reversibly potentiated both in current (197 +/- 15% of control) and voltage-clamp experiments (200 +/- 18% of control). 3. Bath-application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG, 10-300 microM) resulted in a dose-dependent potentiation of NMDA-induced membrane depolarization (up to 400 +/- 33% of control). This potentiation was either prevented by preincubation with (RS)-alpha-methyl-4-carboxyphenylglycine (RS-alpha-MCPG, 300 microM), or blocked when applied immediately after 3,5-DHPG wash-out. 4. Neither (2S,1'S,2'S)2-(2'-carboxycyclopropyl)glycine (L-CCG I, up to 100 microM) nor (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-IV, 1 microM), agonists for group II mGluRs caused any change in NMDA responses. Likewise, L-serine-O-phosphate (L-SOP, 30 microM), agonist for group III mGluRs, did not affect the NMDA-induced depolarization. 5. The enhancement of the NMDA responses was mimicked by phorbol-12,13-diacetate (PDAc, 1 microM) which activates protein kinase C (PKC). The 3,5-DHPG-mediated potentiation of the NMDA-induced depolarization was prevented by preincubation with staurosporine (100 nM) or calphostin C (1 microM), antagonists of PKC. 6. Electrophysiological responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor activation were not affected by agonists for the three-classes of mGluRs. 7. The present data suggest that group I mGluRs exert a positive modulatory action on NMDA responses, probably through activation of PKC. This functional interaction in the striatum appears of crucial importance in the understanding of physiological and pathological events, such as synaptic plasticity and neuronal death, respectively.

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