DISRUPTION OF LEARNING BY EXCITATORY AMINO-ACID RECEPTOR ANTAGONISTS

Compounds that act as competitive or uncompetitive N-methyl-D-aspartat e (NMDA) antagonists, glycine/NMDA-site antagonists, or o-2,3-dihydro- 5-methly-3-oxo-4-isoxalzolepropionic acid (AMPA)-receptor antagonists were evaluated for effects on a repeated acquisition of behavioral cha ins schedule by rats, Responding by rats was maintained by food presen tation under a repeated acquisition or a performance procedure. Under the repeated acquisition procedure, subjects acquired a different thre e-response chain each daily session, Thus, each day a new learning cur ve could be generated for each animal thereby providing a repeated mea sure of learning, Food was presented under a second-order fixed-ratio three (FR3) schedule, Under the performance schedule rats responded un der the same second-order FR3 schedule of food presentation: however, instead of a new sequence being presented each day, the same sequence of responding was required for each daily session. Both the competitiv e (CGS 19755) and uncompetitive (dizocilpine) NMDA antagonists disrupt ed repeated acquisition at doses that did not disrupt performance, In contrast, the glycin/NMDA antagonist MDL 104,653 or the competitive AM PA receptor antagonist LY 293558 did not disrupt acquisition or perfor mance up to doses that suppressed responding. These results suggest th ere are different roles for various excitatory amino acid receptors, o r sites on the NMDA receptor, in the neural bases of learning and that the disruption of acquisition by glutamate antagonists is dependent u pon the particular receptor at which they have activity as well as the particular modulatory site of action.