OPPOSITE PRESYNAPTIC REGULATIONS BY GLUTAMATE THROUGH NMDA RECEPTORS OF DOPAMINE SYNTHESIS AND RELEASE IN RAT STRIATAL SYNAPTOSOMES

Purified striatal synaptosomes were superfused continuously with L-[3,5-H-3]tyrosine to measure simultaneously the synthesis ([H-3]water formed during the conversion of [H-3]tyrosine into [H-3]DOPA) and the release of [H-3]dopamine ([H-3]DA). Glutamate (10(-3) M) and NMDA (10(-3) M, in the absence of Mg2+) stimulated the release of [H-3]DA, but they reduced the efflux of [H-3]water. This reduction of [H-3]DA synthesis was blocked by 2-amino-5-phosphonovalerate indicating the involvement of NMDA receptors. Although D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) and kainate stimulated the release of [H-3]DA, they did not affect its synthesis. The glutamate-evoked inhibition of [H-3]DA synthesis was prevented when synaptosomes were superfused continuously with adenosine deaminase plus quinpirole, a treatment which markedly reduces the phosphorylation of tyrosine hydroxylase by cAMP dependent protein kinase. The opposite effects of glutamate on [H-3]DA synthesis and release were mimicked by ionomycin (10(-6) M). It is proposed that both an activation of a cyclic nucleotide phosphodiesterase and a dephosphorylation of tyrosine hydroxylase linked to the influx of calcium through NMDA receptors is responsible for the inhibition of dopamine synthesis by glutamate and that calcineurin could play a critical role in these processes.