Disruption of learning by excitatory amino acid receptor antagonists

Compounds that act as competitive or uncompetitive N-methyl-D-aspartate (NMDA) antagonists, glycine/NMDA-site antagonists, or alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxalzolepropionic acid (AMPA)-receptor antagonists were evaluated for effects on a repeated acquisition of behavioral chains schedule by rats. Responding by rats was maintained by food presentation under a repeated acquisition or a performance procedure. Under the repeated acquisition procedure, subjects acquired a different three-response chain each daily session. Thus, each day a new learning curve could be generated for each animal thereby providing a repeated measure of learning. Food was presented under a second-order fixed-ratio three (FR3) schedule. Under the performance schedule rats responded under 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 competitive (CGS 19755) and uncompetitive (dizocilpine) NMDA antagonists distrupted repeated acquisition at doses that did not disrupt performance. In contrast, the glycine/NMDA antagonist MDL 104,653 or the competitive AMPA receptor antagonist LY 293558 did not disrupt acquisition or performance up to doses that suppressed responding. These results suggest there are different roles for various excitatory amino acid receptors, or sites on the NMDA receptor, in the neural bases of learning and that the disruption of acquisition by glutamate antagonists is dependent upon the particular receptor at which they have activity as well as the particular modulatory site of action.