fg-9041 and pyrrolidine-2-4-dicarboxylic-acid

We have investigated the effects of perfusion of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) on the endogenous glutamate-evoked changes of extracellular dopamine and alpha-aminobutyric acid (GABA) in the nucleus accumbens of the awake rat. Local infusion of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxilic acid in the nucleus accumbens produced an increase in extracellular concentrations of glutamate, dopamine, and GABA. At the dose of 4 mM, the increase of extracellular glutamate, dopamine, and GABA were 3.73 +/- 0.46 microM (n = 8; p < 0.001), 4.70 +/- 0.92 nM (n = 6; p < 0.001) and 0.36 +/- 0.08 microM (n = 8; p < 0.001), respectively. Perfusion of the NMDA-receptor antagonist CPP attenuated the increases of dopamine by 90% (n = 5; p < 0.001), but enhanced the increases of GABA by 70% (n = 7; p < 0.01). Perfusion of the AMPA-receptor antagonist DNQX did not attenuate the increases of GABA. These results suggest a differential mediation of ionotropic glutamatergic receptors in the actions of endogenous glutamate on extracellular concentration of dopamine and GABA.

Topics: Animals; Dicarboxylic Acids; Dopamine; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Male; Neurotransmitter Uptake Inhibitors; Nucleus Accumbens; Piperazines; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate

This study examined the effects of intrastriatal administration of ionotropic excitatory amino acid receptor antagonists on biochemical markers of excitatory amino acid transmission in the rat striatum. High-affinity glutamate uptake was measured ex vivo on striatal homogenates 15 min after the local administration of either 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA receptor antagonist, or DL-2-amino-5-phosphonopentanoic acid (AP5), a competitive NMDA antagonist, at various doses (10-500 pmol injected). DNQX induced a dose-dependent increase in glutamate uptake rate, related to an increase in the Vmax of the transport process, whereas no significant change in glutamate uptake was detected after AP5 administration. Similar results were obtained from animals subjected to excitotoxic lesion of striatal neurons by kainate administration 15 days before the injection of DNQX or AP5. In a parallel series of experiments using in vivo microdialysis we showed that DNQX (10(-5) M) in the dialysis probe diminished by approximately 30-40% the increases in the concentrations of glutamate and aspartate elicited by L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM). These data suggest that presynaptic glutamate transmission in the rat striatum may undergo facilitatory autoregulatory processes involving ionotropic non-NMDA receptors and highlight the view that transporters for glutamate may be potent regulatory sites for glutamatergic transmission.

Topics: 2-Amino-5-phosphonovalerate; Animals; Binding, Competitive; Biological Transport; Corpus Striatum; Dicarboxylic Acids; Excitatory Amino Acids; Extracellular Space; Female; Glutamic Acid; Microdialysis; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Receptors, Amino Acid