Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Abstract

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.

Interference of anaesthetics with radioligand binding in neuroreceptor studies

“…However, following intracerebroventricular administration (100-500 µg/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. This indicates that there is activation of either a different receptor or a neuronal pathway of unknown pharmacology [5]. Our results are in accordance with these findings since treatment with zoletile mixture did not affect the binding of [ 125 I]PE2I or [ 3 H]-(S)-citalopram, whereas ketamine/xylazine did.…”

The impact of a competitive and a non-competitive NMDA receptor antagonist on dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra

“…It should be stressed, however, that CGP 40116 was effective only at doses which evoked a behavioural (Koek and Colpaert 1990;K o e k et al 1988;L6scher et al 1993;Willetts et al 1990). The observed effects are in contrast to a n u m b e r of data published previously, which failed to demonstrate any effects of competitive N M D A antagonists on the dopaminergic neurotransmission (Bubser et al 1992;K a b u t o et al 1989;Rao et al 1990Rao et al , 1991Svensson et al 1991). At the level of DA metabolism, depending on the applied doses, both drugs, increase the concentration of DA only, or the concentration of DA, D O P A C and HVA.…”

“…Involvement of dopamine (DA) in the above side-effects has been confirmed by studies, which indicate that drugs operating via dopaminergic receptors antagonize some behavioural effects of MK-801 (Maj et al 1991;Wolf et al, 1993). In contrast to MK-801, which coherently enhances the dopaminergic neurotransmission, preliminary data have shown that competitive NMDA antagonists such as AP-5, AP-7, CPP, D-CPPene, CGP 39551, CGP 37849 and CGS 19755 are devoid of effects on dopaminergic neurotransmission (Bubser et al 1992;Kabuto et al 1989;Rao et al 1990Rao et al , 1991Svensson et al 1991), which in turn, is interpreted as evidence for a possible lack of DA-dependent psychotomimetic and abusing PCP-like sideeffects. These initial data, however, seem to disagree with some behavioural observations which indicate that, when given in doses higher than these antagonizing the effects of NMDA, competitive NMDA antagonists might induce effects typical of PCP, such as stereotyped behaviour and locomotion-stimulating effects (Koek and Colpaert 1990;Koek et al 1988;LSscher and Honack 1991a,b;Willetts et al 1990), which, in consequence suggest that at a certain range of doses also competitive NMDA antagonists may evoke PCP-like, undesired side-effects, possibly via a similar mechanism (Willetts et al 1990).…”

Effects of a non-competitive N-methyl-d-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish

“…Tiletamine (2-(ethylamino)-2-(2-thienyl)-cyclohexanone, or CI-634) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist chemically related to ketamine and phencyclidine (PCP) (Chapman and Meldrum, 1989;Olney et al, 1989;Rao et al, 1991a).…”

“…Presently listed as a Schedule III controlled substance, tiletamine causes dose-dependent ataxia and motor stereotypies in animals (Rao et al, 1991a), also demonstrating abuse potential in both experimental (de la Pena et al, 2012;de la Pena et al, 2013) and clinical studies (Morris and Wallach, 2014;Quail et al, 2001).…”