Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR

Sanger, Helen; Hanna, Lydia; Colvin, Ellen M.; Grubisha, Olivera; Ursu, Daniel; Heinz, Beverly A.; Findlay, Jeremy; Vivier, Richard G.; Sher, Emanuele; Lodge, David; Monn, James A.; Broad, Lisa M.

doi:10.1016/j.neuropharm.2012.05.023

Cited by 29 publications

(28 citation statements)

References 42 publications

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“…CBiPES also reduced the bouts of C/T seizures in the pretreatment study. This supports previous work in anxiety models, such as stress-induced hyperthermia, in which CBiPES was found to mimic the effect of LY379268 when administered alone (Fell et al, 2010; Johnson et al, 2005; Sanger et. al., 2012).…”

Section: 4 Discussionsupporting

confidence: 90%

“…Interestingly, CBiPES was more easily dissolved than BINA under our conditions, and while both drugs were entirely dissolved for injection, this cannot be excluded as a possible explanation of the difference in efficacy between these two PAMS. Both of these compounds have been characterized as selective mGluR2 PAMS (Ahnaou et al, 2009; Benneyworth et al, 2007; Bonnefous et al, 2005; Fell et al, 2010; Galici et al, 2006; Johnson et al, 2005, 2003; Sanger et al, 2012). However, off-target effects during seizure activity cannot be excluded.…”

Section: 4 Discussionmentioning

confidence: 99%

“…Also, the effects of Group 2 agonists can be abolished by pretreatment with Group 2 antagonists, revealing the specificity of the drugs and receptor system against seizures (Folbergrová et al, 2001). While it is difficult to specifically target mGluR2 because of a lack of specific agonists, the positive allosteric modulators (PAM) 3’-[[(2-cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1’-biphenyl]-4-carboxylic acid (BINA) and N -[4’-cyano-biphenyl-3-yl)- N -(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) (CBiPES) have pharmacological specificity at mGluR2 (Ahnaou et al, 2009; Benneyworth et al, 2007; Bonnefous et al, 2005; Fell et al, 2010; Galici et al, 2006; Johnson et al, 2005, 2003; Sanger et al, 2012). …”

Section: 1 Introductionmentioning

confidence: 99%

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Activation of Group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus

Caulder¹,

Riegle²,

Godwin³

2014

Epilepsy Research

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Novel treatments for epilepsy are necessary because many epilepsy patients are resistant to medication. Metabotropic glutamate receptors (mGluRs), specifically mGluR 2 and 3, may serve as antiepileptic targets because of their role in controlling synaptic release. In this study, we administered a Group 2 mGluR agonist, LY379268, one of two mGluR2-specific positive allosteric modulators, BINA or CBiPES, or a cocktail of both BINA and LY379268 in a series of experiments using the pilocarpine model of SE. In one study, groups received treatments 15 minutes prior to pilocarpine, while in a second study groups received treatments after SE had been initiated to determine whether the drugs could reduce development and progression of SE. We measured bouts of stage 5 seizures, latency to the first seizure, and the maximum Racine score to characterize the seizure severity. We analyzed mouse EEG with implanted electrodes using a power analysis. We found that pretreatment and posttreatment with LY379268 was effective at reducing both behavioral correlates and power in EEG bandwidths associated with seizure, while CBiPES was less effective and BINA was ineffective. These data generally support continued development of mGluR2 pharmacology for novel antiepileptic drugs, though further study with additional drugs and concentrations will be necessary.

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Section: 4 Discussionsupporting

confidence: 90%

Section: 4 Discussionmentioning

confidence: 99%

Section: 1 Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus

Caulder¹,

Riegle²,

Godwin³

2014

Epilepsy Research

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“…To further assess the ability of mGlu 2 to modulate excitatory transmission, we examined the effect of LY395756 (10 μM), an mGlu 2 partial agonist that also blocks mGlu 3 responses at higher concentrations (Dominguez et al, 2005; Hanna et al, 2013; Sanger et al, 2013), on both electrically-evoked EPSCs and optically-evoked thalamostriatal EPSCs. Surprisingly, five minute bath application of LY395756 produced a striking but reversible inhibition of both electrically-evoked (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

2017

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The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals. We used optogenetic techniques and recently-discovered pharmacological tools to dissect the effects of a prominent presynaptic GPCR, metabotropic glutamate receptor 2 (mGlu2), on corticostriatal vs. thalamostriatal transmission. We found that an agonist of mGlu2 and mGlu3 induces long-term depression (LTD) at synapses onto MSNs from both the cortex and the thalamus. Thalamostriatal LTD is selectively blocked by an mGlu2-selective negative allosteric modulator and reversed by application of an antagonist following LTD induction. Activation of mGlu2/3 also induces LTD of thalamostriatal transmission in striatal cholinergic interneurons (CINs), and pharmacological activation of mGlu2/3 or selective activation of mGlu2 inhibits CIN-mediated dopamine release evoked by selective stimulation of thalamostriatal inputs. Thus, mGlu2 activation exerts effects on striatal physiology that extend beyond modulation of corticostriatal synapses, and has the potential to influence cognition and striatum-related disorders via inhibition of thalamus-derived glutamate and dopamine release.

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“…In support of this latter point, Gjoni et al 135 showed that GABA B (γ-aminobutyric acid type B) receptors desensitize, in terms of both cell-surface expression and signalling, when exposed to saturating concentrations of GABA; however, exposure to a low concentration of GABA plus a PAM (positive allosteric modulator) did not cause apparent desensitization, despite both treatment paradigms resulting in a similar acute response. Another example has been shown in vitro by Sanger et al 136 : rat primary cortical neuronal cultures were incubated overnight with various agonists and PAMs for the group II mGluRs (metabotropic glutamate receptors). In these experiments, the calcium oscillations that were elicited in response to the group II receptor agonist LY379268 and the mGluR2-preferring agonist LY541850 were diminished after overnight incubation with the receptor agonists; however, the responses were not altered when the cultures were incubated with the PAM CBiPES.…”

Section: Figurementioning

confidence: 99%

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

Conn

Lindsley

Meiler

et al. 2014

Nat Rev Drug Discov

239

322

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Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system.

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Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR

Cited by 29 publications

References 42 publications

Activation of Group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus

Activation of Group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

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