The possible involvement of ionotropic and metabotropic quisqualate (QA) receptors in neuronal plasticity was studied in cultured glutamatergic cerebellar or hippocampal cells in terms of the specific activity of phosphate-activated glutaminase, an enzyme important in the synthesis of the putative neurotransmitter pool of glutamate. When cerebellar or hippocampal neurons were treated with QA, it elevated the specific activity of glutaminase in a dose-dependent manner. The half-maximal effect was obtained at about 0.1 microM, the maximum increase was at about 1 microM, but levels higher than 10 microM QA produced progressive reduction in glutaminase activity. In contrast, QA had little effects on the activities of lactate dehydrogenase and aspartate aminotransferase and the amount of protein, indicating that the increase in glutaminase was relatively specific. The QA-mediated increase in glutaminase was mimicked by the ionotropic QA receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; EC50, about 0.5 microM), but not by the metabotropic QA receptor agonist trans-(+-)-1-amino-cyclopentyl-1,3,dicarboxylate (t-ACPD; up to 0.5 mM). The specific ionotropic QA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited QA- and AMPA-mediated increases in glutaminase activity in a dose-dependent manner, whereas other glutamate receptor antagonists, D,L-2-amino-5-phosphonovalerate, gamma-D-glutamyl aminomethyl sulphonic acid and gamma-D-glutamyl diethyl ester were ineffective. The elevation of neurotransmitter enzyme was Ca(2+)-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)