The effects of chronic administration of phencyclidine (PCP) or CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid) on the cataleptic effects of N-methyl-D-aspartate (NMDA) receptor antagonists were studied in pigeons. PCP, a channel blocker of the NMDA receptor complex, or CGS 19755, a competitive NMDA antagonist, was administered i.m. to separate groups of pigeons each day. Tolerance developed to the cataleptic effects in both PCP- and CGS 19755-treated pigeons. PCP tolerance was characterized initially by 5-fold rightward shift and, with an increased chronic PCP dose, a complete downward shift of the PCP dose-effect curve. CGS 19755 tolerance was indicated by a 10-fold rightward shift of its dose-cataleptic effect curve. Cross-tolerance was obtained from PCP to other PCP-like compounds including dizocilpine (MK 801), ketamine, dextrorphan, 1-(2-thienyl)-cyclohexyl-piperidine and [(+)-SKF 10047] [(+)-N-allyl-normetazocine] as well as to the competitive NMDA antagonist, CGS 19755. Cross-tolerance also developed from CGS 19755 to another competitive NMDA antagonist, CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] as well as to PCP-like compounds. The pharmacological selectivity of tolerance was evident because there was equal sensitivity to etomidate or pentobarbital in tolerant and nontolerant pigeons. The symmetric cross-tolerance between PCP-like compounds and competitive NMDA antagonists suggests the cataleptic effects of the two classes of NMDA antagonists are probably mediated via a similar mechanism of inhibition of neurotransmission at the NMDA excitatory synapse.