Metabotropic Glutamate Receptors Regulate<i>N</i>-Methyl-<scp>d</scp>-Aspartate–Mediated Synaptic Transmission in Nucleus Accumbens

Abstract

We recorded intracellularly from core nucleus accumbens (NAcc) neurons in brain slices to study the regulation by metabotropic glutamate receptors (mGluRs) of pharmacologically isolated N-methyl--aspartate-mediated excitatory postsynaptic currents (NMDA-EPSCs). Monosynaptic NMDA-EPSCs, evoked by local stimulation, were isolated by superfusion of the non-NMDA and gamma-aminobutyric acid-A (GABAA) receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) and bicuculline (15 microM), respectively. Trans-1-aminocyclopentane-1,3-decarboxylic acid (trans-ACPD; 50 microM), a nonspecific group 1 and 2 mGluR agonist, had no effect on resting membrane potential (RMP) or input resistance of NAcc neurons. However, it consistently decreased NMDA-EPSC areas (time integrals) dose dependently (1-100 microM; EC50 = 8 microM) and reversibly. The specific group 1 mGluR agonists quisqualate (1-4 microM) and (RS)-3, 5-dihydroxyphenylglycine (DHPG; 100 microM) did not mimic the trans-ACPD effect on NMDA-EPSCs, nor did exposure of the slice to the group 1 mGluR antagonist (+)-2-amino-3-phosphonopropionic acid (-AP3, 0.4 mM) inhibit the trans-ACPD effect. The putative mGluR1 and mGluR2 antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) at 0.5 mM failed to antagonize trans-ACPD effects but at 1 mM blocked them. Both the group 2 mGluR agonist (2S,3S, 4S)-alpha-(carboxycyclopropyl)-glycine (-CCG-I, 2 microM) and the group 3 mGluR specific agonist (+)-2-amino-4-phosphonobutyric acid (-AP4, 20 microM) attenuated NMDA-EPSC areas; the effect of -AP4 was blocked by the group 3 antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4; 0.5 mM). Exogenously applied NMDA, in the presence of tetrodotoxin to prevent presynaptic effects, induced inward currents that were decreased by 20 microM -AP4 but not by 10 microM trans-ACPD. These findings suggest that NMDA receptor-mediated neurotransmission in NAcc is under dual inhibitory regulation by group 2 and 3 metabotropic receptor subtypes: -AP4-sensitive receptors located postsynaptically and those sensitive to trans-ACPD located presynaptically.