In vivo modulation of the N-methyl-D-aspartate receptor complex by D-serine: potentiation of ongoing neuronal activity as evidenced by increased cerebellar cyclic GMP.

Direct intracerebellar injections of N-methyl-D-aspartate (NMDA) or D-serine elicited dose-dependent increases in cerebellar cyclic GMP levels, in vivo in the mouse. The actions of D-serine were antagonized by the competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid and by the phencyclidine receptor agonist MK-801, observations supporting actions at the NMDA-coupled glycine receptor. In addition, the actions of D-serine were antagonized by a partial agonist (D-cycloserine) and an antagonist (HA-966) of the NMDA-coupled glycine receptor. These data are all consistent with D-serine acting at the NMDA-coupled glycine receptor and represent the first demonstration of glycine receptor potentiation of ongoing NMDA-mediated neuronal activity in the CNS, rather than potentiation of exogenous NMDA.