1-Hydroxy-3-aminopyrrolid-2-one (HA-966) and kynurenate antagonize [formula omitted] induced enhancement of [ 3H]dopamine release from rat striatal slices

Abstract

Excitatory amino acid receptors, including those of conventional N- methyl- d- aspartate (NMDA) type, are believed to be located on terminals of the nigrostriatal dopaminergic projection in the rat. Activation of these receptors enhances depolarization-induced dopamine release. Rat striatal slices were preloaded with [ 3H]dopamine (DA) and its subsequent release and possible modulation during excitatory amino acid receptor activation were investigated. Superfusion of slices with K + (20 mM) produced a robust increase in [ 3H]DA release, which was markedly enhanced by the inclusion of N-methyl- d-aspartate (NMDA) or NMDLA in the buffer. No enhancement was observed following addition of glycine, suggesting that either the glycine binding site on the NMDA receptor complex was lacking, or that it was tonically fully activated. The latter appears to be the case since 1-hydroxy-3-aminopyrrolid-2-one (HA-966) (a purported antagonist at strychnine-insensitive glycine receptors) was able to antagonize the NMDA-induced enhancement of [ 3H]dopamine release. This action of HA-966 could subsequently be reversed by inclusion of glycine in the medium. While the action of NMDA was readily prevented by the inclusion of the competitive antagonist 2-amino-7-phosphonoheptanoate (AP7), this antagonism could not be reversed by either glycine or d-serine. Kynurenate behaved in an apparently identical manner to HA-966. Strikingly, the enhancement of dopamine release by kainate was unaffected by HA-966. These data indicate that NMDA receptor-mediated enhancement of [ 3H]DA release from striatal dopaminergic terminals can be modulated through strychnine-insensitive sites.