Investigating the role of mGluR2 versus mGluR3 in antipsychotic-like effects, sleep-wake architecture and network oscillatory activity using novel Han Wistar rats lacking mGluR2 expression

Christian M Wood,Keith A Wafford,Andrew P Mccarthy,Nicola Hewes,Elaine Shanks,David Lodge,Emma S.J Robinson

doi:10.1016/j.neuropharm.2018.07.013

Christian M Wood, Keith A Wafford + Show 5 more

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https://doi.org/10.1016/j.neuropharm.2018.07.013

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Abstract

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep-wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands.The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine- and phencyclidine-induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose-dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake-promoting effects in both rat strains, albeit smaller in the mGluR2-lacking Han Wistar rats, indicating both mGluR2 and mGluR3-mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4–9 Hz) and gamma (30–80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats.Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic-like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations.

Highlights

IntroductionModulation of glutamate neurotransmission through group II metabotropic glutamate receptors (mGluR2 and metabotropic glutamate receptor 3 (mGluR3)) is an area of promise for the treatment of psychiatric and neurological disorders (Niswender and Conn, 2010; Nicoletti et al, 2011; Chaki et al, 2013; Li et al, 2015)
Modulation of glutamate neurotransmission through group II metabotropic glutamate receptors is an area of promise for the treatment of psychiatric and neurological disorders (Niswender and Conn, 2010; Nicoletti et al, 2011; Chaki et al, 2013; Li et al, 2015). These receptors are primarily considered as auto- and hetero-receptors that reduce the release of Abbreviations: EEG, electroencephalography; mGluR2, metabotropic glutamate receptor 2; mGluR3, metabotropic glutamate receptor 3; HFO, high frequency oscillations; Grm2, glutamate receptor metabotropic 2
We recently reported on a novel Han Wistar rat strain containing a nonsense mutation in the Grm2 gene that leads to a loss of mGluR2 expression (Wood et al, 2017)

Summary

Introduction

Modulation of glutamate neurotransmission through group II metabotropic glutamate receptors (mGluR2 and mGluR3) is an area of promise for the treatment of psychiatric and neurological disorders (Niswender and Conn, 2010; Nicoletti et al, 2011; Chaki et al, 2013; Li et al, 2015). Neurotransmitters such as glutamate and GABA (Di Iorio et al, 1996; Jones et al, 1998; Cartmell and Schoepp, 2000; Smolders et al, 2004) These actions occur through inhibitory Gai/o signaling that reduces cAMP formation and modulates pathways such as PKA and ERK/MAPK (Tanabe et al, 1992; Pin and Duvoisin, 1995; Harris et al, 2004).

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