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

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 mGlu1 receptor antagonists [2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one] (CFMTI), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-α]benzimidazole-2-carboxamide hydrochloride (YM-298198), and (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685). There was no effect after treatments with the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu2/3 receptor agonist (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the mGlu7 receptor agonist N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the mGlu7 receptor antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), or the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG). These findings indicate that inhibition of mGlu1 receptor selectively increases prepulse inhibition in DBA/2J mice and suggest that mGlu1 receptor antagonists could be a novel treatment for some aspects of schizophrenia.