In vivo 2-amino-3-phosphonopropionic acid administration to neonatal rats selectively inhibits metabotropic excitatory amino acid receptors ex vivo in brain slices

Abstract

In previous work we found that 2-amino-3-phosphonopropionic acid, the ?-phosphono-substituted analog of aspartic acid, is a selective in vitro inhibitor of the excitatory amino acid agonist [ibotenate, quisqualate, trans(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD)]-stimulated phosphoinositide hydrolysis. Here we investigated if the inhibitory effects of 2-amino-3-phosphonopropionic acid on metabotropic excitatory amino acid receptors could be observed in the ex vivo brain slice following in vivo administration to neonatal rats. In vitro addition of 2-amino-3-phosphonopropionic acid noncompetitively antagonized trans-ACPD-stimulated [(3)H]phosphoinositide hydrolysis in hippocampal slices from 9-day-old rats. Intraperitoneal (i.p.) administration of 2-amino-3-phosphonopropionic acid (250, 500 and 750 mg/kg) for two consecutive days (at 7 and 8 days of age) also produced dose-related inhibition of trans-ACPD-stimulated [(3)H]phosphomositide hydrolysis in hippocampal slices from 9-day-old rats. 2-Amino-3-phosphonopropionic acid (500 mg/kg x 2) inhibited quisqualate, ibotenate, and glutamate activations of [(3)H]phosphoinositide hydrolysis, but had no effect on carbachol or norepinephrine stimulations. Thus, multiple in vivo dosing with 2-amino-3-phosphonopropionic acid produces selective inhibition of excitatory amino acid, but not nonexcitatory amino acid receptors coupled to phosphoinositide hydrolysis. 2-Amino-3-phosphonopropionic acid dosing could be used to inhibit the metabotropic excitatory amino acid receptor in vivo to study its function in the developing brain.