Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: Structure-activity studies

The excitatory amino acid antagonists d,l-2-amino-5-phosphonovalerate (d,l-AP5), its isomers d-(-)-AP5 and l-(+)-AP5, d,l-2-amino-4-phosphonobutyrate (AP4), d,l-2-amino-7-phosphonoheptanoate (AP7), β-d-aspartylaminomethylphosphonic acid (ASP-AMP), cis-2,3-piperidinedi-carboxylic acid (cis-PDA), and γ-d-glutamylaminomethylsulphonic acid (GAMS) were tested for their ability to produce a phencyclidine (PCP)-like catalepsy in pigeons when administered intracerebro-ventricularly. Each of the antagonists produced catalepsy, although l-AP5, and the non-selective antagonists GAMS and cis-PDA, produced the effect only at toxic doses. The rank order of potency to produce catalepsy was AP7 > d-AP5 > d,l-AP5 > cis-pda > ASP-AMP > AP4 > l-AP5 > GAMS; there was a strong positive correlation between this rank order of potency vivo and the potency order of these compounds in vitro as NMDA antagonists. The antagonists did not displace significant amounts of [³H]N[1-(2-thienyl)cyclohexyl]piperidine (a congener of phencyclidine) from its recognition site in the brain of pigeon. Thus, the PCP-like catalepsy that is produced by the excitatory neurotransmission at NMDA-preferring receptors that are distinct from, but related to, PCP receptors. The results strongly support the hypothesis that a reduction of neurotransmission at excitatory synapses, utilizing NMDA-preferring receptors, may underlie catalepsy in pigeons induced by PCP.