The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

Abstract

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0-10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5-4.0 mg/kg; subcutaneously (s.c.)) and ( + )-MK-801 (0.03-0.25 mg/kg; s.c.), or low-moderate affinity, ketamine (2.0-16.0 mg/kg; s.c.) and memantine (0.15-20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

“…Thus, improving effects of CFMTI on NMDA antagonist-induced behavioral alterations are compatible with our working hypothesis, expanding the use of CFMTI to dopaminergic-independent neuronal control of psychiatric behavior. In support of this idea, an mGluR5 antagonist was reported to impair social interaction in rats (Koros et al, 2007). Melendez et al (2005) reported that DHPG administered by reverse microdialysis into mPFC elicited glutamate release that was blocked by coapplication of (R,S)-1-aminoindan-1,5-dicarboxylic acid and LY367385 with DHPG, suggesting that mGluR1 in mPFC may play a role in regulating glutamate release.…”

In vitro characterisation of the novel positive allosteric modulators of the mGlu5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat

“…MPEP has been shown to potentiate NMDA receptor antagonist deficits in learning and memory (Homayoun et al, 2004;Campbell et al, 2004), while high doses of MPEP alone will impair DMTP and water maze performance (Ballard et al, 2005). The related mGlu 5 receptor antagonist MTEP has also been shown to induce social isolation in rats (Koros et al, 2007). On the other hand, mGlu 5 PAMs have been shown to have some positive effects on cognition.…”

Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats

“…Defense behaviors relevant to depression were evaluated in a forced swimming test, scoring the total duration of immobility and swimming during a 5-min test session in glass cylinders containing water, as previously described [14]. Social interaction was evaluated as previously described [19,20] by measuring the amount of time spent by each rat in a pair sniffing, grooming, following, kicking, mounting, jumping on, wrestling/boxing, and crawling under/over the partner during a 10-min period of interaction. Anxiety-like behavior was evaluated using an elevated plus-maze by measuring during 5 [14].…”