Metabotropic Glutamate Subtype 5 Receptors 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. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 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 mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 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 mGluR5 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.

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…Our results confirmed previous findings showing that mGluR5 À/À mice have a PPI deficit (Henry et al, 1999;Brody et al, 2004a, b;Kinney et al, 2003) that could not be impaired further by MK-801. We go on to show that the PPI deficit of mGluR5 À/À mutants was completely restored by CX546 facilitated LI in control C57BL/6J mice under conditions, which parametrically disrupted LI, when given only in the conditioning session.…”

“…A functional interactions between mGluR5 and NMDAR is well supported by the literature (Salter and Kalia, 2004) and our own data (Jia et al, 1998;Huang et al, 2001;Hannan et al, 2001). Indeed, several observations have shown that agonists and antagonists of mGluR5 may, respectively, attenuate and potentiate the effects of NMDAR antagonists in vivo (Kozela et al, 2003;Kinney et al, 2003;Homayoun et al, 2004). As mGluR5 antagonist administered alone could not disrupt PPI, but could enhance the effects of PCP (Kinney et al, 2003), it is possible that the PPI deficit in mGluR5 mutants might result from an interaction between NMDAR hypofunction together with missing mGluR5 complex rather than the alternative of only a parallel pathway downstream of mGluR5.…”

“…Indeed, several observations have shown that agonists and antagonists of mGluR5 may, respectively, attenuate and potentiate the effects of NMDAR antagonists in vivo (Kozela et al, 2003;Kinney et al, 2003;Homayoun et al, 2004). As mGluR5 antagonist administered alone could not disrupt PPI, but could enhance the effects of PCP (Kinney et al, 2003), it is possible that the PPI deficit in mGluR5 mutants might result from an interaction between NMDAR hypofunction together with missing mGluR5 complex rather than the alternative of only a parallel pathway downstream of mGluR5. The regulation of NMDAR is very complex and the present study did not dissect molecular pathways underlying NMDAR functional changes in mGluR5 À/À mouse.…”

“…Deficits in PPI have been reported in schizophrenia (Swerdlow et al, 1994;Braff et al, 2001), in patients with Huntington's disease , Tourett's syndrome (Castellanos et al, 1996), and obsessive-compulsive disorder (Swerdlow and Geyer, 1993). The mGluR5 À/À mice exhibited robust PPI deficits found in different laboratories (Henry et al, 1999;Brody et al, 2004a, b;Kinney et al, 2003) using mice on three different background strains, based on procedures with different stimuli modalities and startle magnitudes. However, the observed PPI deficit in mGluR5 À/À mice was resistant to the antipsychotics (Brody et al, 2004b), suggesting that these mice cannot serve as a model with predictive validity to test for typical/atypical antipsychotic drug effects and may model some other psychiatric disorder (Brody et al, 2004b).…”

“…The mGluR5 binds through G-dependent or independent pathways (Heuss et al, 1999) with predominantly couple via Gq to phospholipase C. This yields diacylglycerol, which activates protein kinase C (PKC), and inositol-1,4,5-triphosphate, which releases intracellular Ca 2 + (Conn and Pin, 1997), and this in turn can increase NMDAR-evoked responses in a variety of neuronal tissues (Doherty et al, 1997;Awad et al, 2000), indicating one potential functional link between mGluR5 and NMDAR. Indeed, administration of mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyradine (MPEP) facilitated in vivo effects of NMDAR antagonists in rodents, producing anxiolytic (Spooren et al, 2000), neuroprotective (Bruno et al, 2000), and anticonvulsant (Chapman et al, 2000) effects, disrupting prepulse inhibition (PPI) (Kinney et al, 2003) and enhancing the detrimental effects of MK-801 on cognition and stereotypy (Homayoun et al, 2004). This demonstrates that mGluR5 play a major role in regulating NMDAR-dependent function.…”