Effects of (+)-HA-966, CGS-19755, phencyclidine, and dizocilpine on repeated acquisition of response chains in pigeons: Systemic manipulation of central glycine sites

The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, its enan tiomer (-)-HA-966, the competitive glutamate antagonist CGS-19755, the unco mpetitive glutamate antagonists phencyclidine and dizocilpine, and the mu o pioid agonist morphine were evaluated in a repeated acquisition task in pig eons. All of the drugs produced dose-dependent decreases in rates of respon ding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to hav e a greater effect on acquisition than did morphine at doses that did not f ully suppress responding. The rate suppression and learning impairment prod uced by a large dose of (+)-HA-966 (100 mg/kg) were completely prevented by coadministration of the glycine-site agonist D-serine (560 mg/kg) but not by its enantiomer, L-serine (1000 mg/kg). D-Serine, however, produced incom plete antagonism of the effects of dizocilpine and phencyclidine and failed to alter those of CGS-19755. These findings provide evidence that reducing the activity of the NMDA subtype of the glutamate receptor through pharmac ological action at any of three sites produces similar decrements in acquis ition, and those produced through antagonism of the glycine site are differ entially sensitive to the glycine-site agonist D-serine.