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

Friday, September 4, 2009

Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ, Conn PJ.
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 (mGIuRS) enhances NMDAR-mediated currents in vitro. Thus, activation of mGIuR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGIuR5, the present study examined the effects of mGIuR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined
PPI in mGIuR5 knockout mice. Finally, we examined PPI after administration of the mGIuR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGIuR5 antagonist 2-methyl-6-(phenylethynyl)pyridine 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 mGIuR5 knockout mice display consistent deficits in PPI relative to their wild-type 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.
For more information on this study, please refer to:
J Pharmacol Exp Ther. 2003 Jul;306(1):116-23. Epub 2003 Mar 26.

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