Glycine, glycinamide and D-serine act as positive modulators of signal transduction at the N-methyl-D-aspartate (NMDA) receptor in vivo: differential effects on mouse cerebellar cyclic guanosine monophosphate levels.

Direct intracerebellar (icb) administration of glycine, glycinamide and D-serine produced time- and dose-dependent changes in mouse cerebellar cGMP levels, indicating a modulation of ongoing neuronal activity through the NMDA receptor complex. Intracerebroventricular administration of glycinamide also produced a time-dependent change in cGMP levels, indicating a central mechanism of action. The icb dose-response data indicated a unimolecular interaction for these compounds. D-serine-, glycine-, and glycinamide-mediated increases in cGMP levels were reversed by the competitive NMDA antagonist, CPP and the NMDA-associated glycine receptor antagonist, HA-966, indicating mediation via the NMDA receptor complex. Glycine and D-serine were less effective than glycinamide at increasing cerebellar cGMP levels. In contrast, L- and D-serinamide did not affect cGMP levels. These results indicate that glycine receptor is not saturated under physiological conditions and also suggest possible existence of multiple glycine pools.