Received for publication January 2, 2003.
Revised February 6, 2003.
Accepted for publication March 20, 2003.

Metabotropic Glutamate Subtype 5 Receptors (mGluR5) Modulate Locomotor Activity and Sensorimotor Gating in Rodents

Abstract

Use-dependent N-methyl-D-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. In order to further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without co-administration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition of the acoustic startle response (PPI) in rodents. We further examined PPI in mGluR5 knock-out mice. Finally, we examined PPI following administration of the mGluR5 agonist, CHPG, alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist, MPEP, has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knock-out mice display consistent deficits in PPI relative to their wildtype controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.

Key words: CHPG, MPEP, Metabotropic receptors, Prepulse inhibition, Schizophrenia, mGluR5

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