Modulation of glutamate receptors by phencyclidine and glycine in the rat cerebellum: cGMP increase in vivo.

In rats receiving N-methyl-D-aspartate (NMDA) intraventricularly or intracisternally the cerebellar cyclic guanosine monophosphate (cGMP) content increases in a dose-related manner. This response was used to study phencyclidine (PCP) and glycine interactions with the glutamate receptor subtype stimulated by NMDA. The increase of cGMP elicited by NMDA was inhibited by PCP and potentiated by glycine. Moreover, 2-amino-5-phosphonovalerate (APV) abolished the NMDA response. Since the increase in cerebellar cGMP induced by kainate, a synthetic agonist of another glutamate receptor subtype, was not modified by APV, the specificity of its action on NMDA response was confirmed. The increase of cerebellar cGMP content elicited by glycine was inhibited by PCP and APV but not by strychnine. Binding studies failed to demonstrate an apparent competitive interaction between PCP, glycine and NMDA. This suggests that the observed interaction is not of the isosteric type. The present results provide evidence that glycine, in vivo, acting at strychnine-insensitive recognition sites modulates allosterically in a positive manner the function of NMDA-sensitive glutamate receptors.