Vol. 289, Issue 1, 521-527, April 1999

Effects of (+)-HA-966, CGS-19755, Phencyclidine, and Dizocilpine on Repeated Acquisition of Response Chains in Pigeons: Systemic Manipulation of Central Glycine Sites^1,2

Cory M. Campbell³ , Eduardo R. Butelman⁴ and James H. Woods

Departments of Pharmacology (C.M.C., E.R.B., J.H.W.) and Psychology (J.H.W.), University of Michigan, Ann Arbor, Michigan

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 enantiomer ()-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the µ opioid agonist morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have a greater effect on acquisition than did morphine at doses that did not fully suppress responding. The rate suppression and learning impairment produced 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 incomplete 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 pharmacological action at any of three sites produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the glycine-site agonist D-serine.