Metabotropic glutamate receptors regulate N-methyl-D-aspartate-mediated synaptic transmission in nucleus accumbens

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-D-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-4 (GABA(A)) receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 mu M) and bicuculline (15 mu M), respectively. Trans-1-aminocyclopentane- 1,3-decarboxylic acid (trans-ACPD: 50 mu M), 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 mu M; EC50 = 8 mu M) and reversibly. The specific group 1 mGluR agonists quisqualate (1-4 mu M) and (RS)-3,5-dihydroxyphenylglycine (DHPG; 100 mu M) did not mimic the trans-ACPD effect on NMDA-EPSCs, nor did exposure of the slice to the group 1 mGluR antagonist L(+)-2-amino-3-phosphonopropionic acid (L-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 (L-CCG-I, 2 mu M) and the group 3 mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 20 mu M) attenuated NMDA-EPSC areas; the effect of L-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 tetrodoxin to prevent presynaptic effects, induced inward currents that were decreased by 20 mu M L-AP4 but not by 10 mu M 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: L-AP4-sensitive receptors located postsynaptically and those sensitive to trans-ACPD located presynaptically.