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Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N ‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites
Author(s) -
Rao Tadimeti S.,
Contreras Patricia C.,
Cler Julie A.,
Mick Steve J.,
Dilworth Vickie M.,
Iyengar Smriti,
Monahan Joseph B.,
Wood Paul L.
Publication year - 1991
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1991.tb02005.x
Subject(s) - phencyclidine , nmda receptor , dizocilpine , chemistry , agonist , neurochemical , pharmacology , kainate receptor , psychotomimetic , receptor , medicine , endocrinology , biology , ampa receptor , biochemistry
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 [ 3 H]1‐(2‐thienyl)cyclohexylpiperidine with an IC 50 of 79 n M without affecting σ ‐ , 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[ 3 H]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 μg/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.