Actions of d-cycloserine at the N-methyl-d-aspartate-associated glycine receptor site in vivo

The antibiotic, d-cycloserine has been shown to be a partial agonist at the N-methyl-d-aspartate (NMDA)-coupled, strychnine-insensitive glycine receptor by in vitro receptor binding. This partial agonism was further investigated in an in vivo system, by monitoring changes in levels of cyclic guanosine-monophosphate (cGMP), a well characterized second messenger response, mediated by the NMDA receptor complex, in the cerebellum of the mouse. Parenteral injections of d-cycloserine produced a biphasic dose-response curve which suggested partial agonism. In support of this contention, when intracerebellar injections were made together with d-serine, a glycine agonist, d-cycloserine attenuated the N-methyl-d-aspartate receptor-mediated increase in levels of cGMP. Likewise, systemic administration of d-cycloserine attenuated increases in cGMP induced by pentylenetetrazol. These data are relevant to the study of N-methyl-d-aspartate-mediated neurotransmission, since d-cycloserine is a parenterally bioavailable compound, with both agonist and depressant properties at the N-methyl-d-aspartate-associated glycine receptor.