Metabotropic Glutamate Receptors Regulate N-Methyl-D-Aspartate-Mediated
Synaptic Transmission in Nucleus Accumbens.
Gilles Martin, Zhiguo Nie and George R. Siggins.
The Scripps Research Institute, Department of Neuropharmacology, 10550 N.
Torrey Pines Rd. La Jolla, CA 92037, USA.
APStracts 4:202N, 1997.
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-D-aspartate-mediated
excitatory postsynaptic currents (NMDA-EPSCs). Monosynaptic NMDA-EPSCs, evoked
by local stimulation, were isolated by superfusion of the non-NMDA and GABAA
receptor antagonists, CNQX (6-cyano-7-nitroquinoxaline- 2,3-dione; 10 mM) and
bicuculline (15 mM), respectively. Trans- 1-aminocyclopentane-1,3-decarboxylic
acid (trans-ACPD; 50 mM), a non-specific 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 mM; EC50 = 8 mM) and reversibly. The specific group 1
mGluR agonists quisqualate (1-4 mM) and DHPG ((RS)-3,5-dihydroxyphenylglycine;
100 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 (+)--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)--(carboxycyclopropyl)-glycine (L-CCG-I, 2 mM) and the
group 3 mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 20
mM), attenuated NMDA-EPSC areas; the effect of L-AP4 was blocked by the group
3 antagonist MAP4 ((S)-2-amino-2-methyl-4-phosphonobutanoic acid, 0.5 mM).
Exogenously-applied NMDA, in the presence of tetrodotoxin to prevent
presynaptic effects, induced inward currents that were decreased by 20 mM L-
AP4 but not by 10 mM 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.
Received 7 May 1997; accepted in final form 18 August 1997.
APS Manuscript Number J373-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 28 August 1997