1. ¹Department of CNS Research, Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
2. ²Genomics Group, Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
3. ³Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Warsaw, Poland

Correspondence: Dr E Koros, Department of CNS Research, Boehringer-Ingelheim Pharma GmbH & Co. KG, 65 Birkendorfer Strasse, D-88397 Biberach, Germany. Tel: +49 7351 54 97876; Fax: +49 7351 54 98928; E-mail: Eliza.Koros@bc.boehringer-ingelheim.com

⁴Current address: Bionomics Ltd Europe, Rue Jean Sapidus, Parc d'Innovation, F-67400 Illkirch, France

Received 28 November 2005; Revised 26 April 2006; Accepted 15 May 2006; Published online 14 June 2006.

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.