Contrasting neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate-coupled and -uncoupled PCP recognition sites.
Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate (NMDA)-coupled and -uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [3H]1-(2-thienyl)cyclohexylpiperidine with an IC50 of 79 nM without affecting sigma-, glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA-coupled PCP recognition sites, tiletamine decreased basal, harmaline-, and D-serine-mediated increases in cyclic cGMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3-hydroxy[3H]PCP to its high-affinity NMDA-uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK-801), ketamine, PCP, dexoxadrol, and 1-(2-thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA-uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK-801-induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA-uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100-500 micrograms/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. These data indicate a differential interaction of tiletamine with the NMDA-coupled and -uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology.
Rao
T S
TS
CNS Diseases Research, G. D. Searle-Monsanto, St. Louis, Missouri 63198.
Contreras
P C
PC
Cler
J A
JA
Mick
S J
SJ
Dilworth
V M
VM
Iyengar
S
S
Monahan
J B
JB
Wood
P L
PL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D009833:Olfactory Pathways / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D013992:Tiletamine / Q000378:metabolism* / Q000494:pharmacology
D008024:Ligands; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D013992:Tiletamine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D006152:Cyclic GMP; D010622:Phencyclidine; D004298:Dopamine