title: Tolerance to the cataleptic effect of the N-methyl-D-aspartate (NMDA) receptor antagonists in pigeons: cross-tolerance between PCP-like compounds and competitive NMDA antagonists.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: C P
authors.initials: CP
authors.lastname: France
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D010856:Columbidae / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005045:Etomidate / Q000494:pharmacology; D005123:Eye / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007273:Injections, Intramuscular; D009126:Muscle Relaxation; D010424:Pentobarbital / Q000494:pharmacology; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D006993:Hypnotics and Sedatives; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; C053672:selfotel; D010424:Pentobarbital; D010622:Phencyclidine; D005045:Etomidate