Pharmacological effects of metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice

Abstract

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animals using acoustic prepulse inhibition of the startle. Both classical and atypical antipsychotics have been shown to improve prepulse inhibition in DBA/2J mice, a non-pharmacological model for impaired sensorimotor gating. The purpose of the present study was to clarify whether metabotropic glutamate receptors participate in control of sensorimotor gating. We evaluated various metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. This basal level of prepulse inhibition in DBA/2J mice was increased by only the mGlu 1 receptor antagonists [2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1 H-1,2,3-triazol-4-yl]-2,3-dihydro-1 H-isoindol-1-one] (CFMTI), 6-amino- N-cyclohexyl- N,3-dimethylthiazolo[3,2-α]benzimidazole-2-carboxamide hydrochloride (YM-298198), and (3,4-dihydro-2 H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685). There was no effect after treatments with the mGlu 5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu 2/3 receptor agonist (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu 2/3 receptor antagonist (2 S)-2-amino-2-[(1 S,2 S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the mGlu 7 receptor agonist N,N ′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the mGlu 7 receptor antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5- c]pyridin-4(5 H)-one (MMPIP), or the mGlu 8 receptor agonist ( S)-3,4-dicarboxyphenylglycine (DCPG). These findings indicate that inhibition of mGlu 1 receptor selectively increases prepulse inhibition in DBA/2J mice and suggest that mGlu 1 receptor antagonists could be a novel treatment for some aspects of schizophrenia.