N-methyl-D-aspartate antagonists and drug discrimination

Excitatory amino acids (EAA), such as glutamate, are thought to be involved in various disorders (e.g., ischemic brain damage, epilepsy, Parkinson's disease), and EAA antagonists have been suggested as potential treatments for these disorders. Phencyclidine (PCP), with produces psychotomimetic effects in humans, has antagonist properties at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors that have been suggested to underlie some of its actions. This suggestion, and concern about possible psychotomimetic activity, has stimulated research aimed at examining to what extent the behavioral profile of other NMDA antagonists resembles that of PCP. Drug discrimination (DD) is prominent among the procedures used to carry out such comparisons. The results of clinical studies with NMDA antagonists provide feedback about the predictive validity of the DD procedures used to characterize their preclinical behavioral profile. Further, DD is used also to examine the ability of compounds to attenuate the discriminative stimulus (DS) effects of PCP-type drugs, and results of such studies have been suggested to provide evidence of antipsychotic potential. Finally, although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.