Interactions between N-methyl-D-aspartate and CGS 19755 administered intramuscularly and intracerebroventricularly in pigeons

Behavioral effects of N-methyl-D-aspartate (NMDA) and the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidinecarboxylic acid (CGS 19755) were studied in pigeons. NMDA decreased responding under a fixed-ratio schedule of food presentation and was 8000 times more potent administered intracerebroventricularly (i.c.v.) as compared to intramuscularly (i.m.). CGS 19755 was 870 times more potent in producing catalepsy when administered i.c.v.; however, the duration of catalepsy was similar by the two routes of administration. Administered i.m. CGS 19755 decreased response rates only at doses that also produced catalepsy; administered i.c.v. some doses of CGS 19755 decreased responding without producing other behavioral effects. Rate-decreasing effects of i.m. NMDA were attenuated by i.m. CGS 19755; however, when CGS 19755 was administered i.c.v., there was little or no antagonism of NMDA. Rate-decreasing effects of i.c.v. NMDA were not attenuated by i.m. or i.c.v. CGS 19755 up to doses that produced catalepsy or eliminated responding. The large difference in potency between i.m. and i.c.v. administration for NMDA and for CGS 19755, as well as the slower onset of catalepsy when CGS 19755 was administered i.m., suggests these compounds do not readily cross the blood-brain barrier when administered parenterally. The inability of CGS 19755 to attenuate the rate-decreasing effects of NMDA when CGS 19755 or NMDA was administered i.c.v. suggests NMDA might decrease responding by different mechanisms when administered i.m. or i.c.v. in pigeons. Together these results indicate antagonism of NMDA in this study, and perhaps in other studies, when both NMDA and CGS 19755 were administered parenterally, might result from a peripherally mediated interaction. Moreover, this agonist-antagonist interaction is not a simple, competitive antagonism.