The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia

Brown, Jessica H.; Iacovelli, Luisa; Cicco, Gabriele Di; Grayson, Ben; Rimmer, Lauren; Fletcher, Jennifer; Neill, Joanna C.; Wall, Mark J.; Ngomba, Richard Teke; Harte, Michael K.

doi:10.1016/j.neuropharm.2022.108982

Cited by 6 publications

(7 citation statements)

References 74 publications

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“…As anticipated from previous research, scPCP animals displayed significantly impaired NOR performance compared to scVehicle rats [ 36 , 54 ]. As reviewed by Neill et al [ 55 ], the NOR paradigm assesses visual recognition memory, one of the seven cognitive domains fundamentally impaired in schizophrenia as identified by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative.…”

Section: Discussionsupporting

confidence: 80%

“…However, no significant difference in locomotor activity (the total number of line crossings across both trials) was found between the scVehicle and scPCP treatment groups ( Figure 2 E). Thus, as previously reported, the scPCP model exhibits specific disruption of NOR performance without locomotor deficits [ 36 ].…”

Section: Resultssupporting

confidence: 72%

“…mGlu5 receptor PAMs have been demonstrated to enhance cognitive performance, improve recognition memory, attenuate avoidance response, and reduce impulsivity in the five-choice serial reaction time task in rodents [ 31 , 32 , 33 , 34 , 35 ]. We have shown that the potent, selective mGlu5 receptor PAMs VU0409551 and VU0360172 significantly reverse cognitive deficits in the scPCP rat model for schizophrenia [ 36 ] and they are also efficacious in acute psychosis models [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…An early study into this selectivity demonstrated that whilst both mGlu5 receptor PAMs DFB and CPPHA induced intracellular calcium release, they induced differential effects on ERK1/2 signalling [ 46 ]. We previously showed VU0409551 and VU0360172 to exhibit divergent effects on scPCP-induced increases in PFC AKT and MAPK phosphorylation, with VU0409551 inducing a significant alteration in expression of p-AKT, and VU0360172 modifying p-MAPK levels [ 36 ]. Other publications support the hypothesis that these PAMs differ in their modulation of mGlu5 receptor-linked signalling pathways: VU0409551 did not modulate pERK1/2 levels in the hippocampus or PFC when dosed chronically and was biased away from the PKC/pERK1/2 pathway relative to VU0360172 [ 35 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

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Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Brown

Grayson

Neill

et al. 2023

Cells

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The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine ‘modulation bias’ in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

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Section: Discussionsupporting

confidence: 80%

Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Brown

Grayson

Neill

et al. 2023

Cells

Self Cite

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“…MGlu5 KO mice show alterations in the behavioral domains affected in ASD, such as burial behavior, social interaction, locomotor activity, and anxiety [ 258 ]. Accordingly, alterations in mGlu5 have been associated to diverse neurological and neuropsychiatric disorders, including FXS [ 220 , 259 ], attention-deficit/hyperactivity ADHD [ 260 ], ASD [ 155 ], schizophrenia [ 261 , 262 ] and epilepsy [ 32 ]. An overactive mGlu5 signaling is thought to be responsible for multiple behavioral features of FXS [ 219 , 220 ].…”

Section: Role Of Glutamatergic Transmission In Asd Pathophysiology: E...mentioning

confidence: 99%

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

Montanari

Martella

Bonsi

et al. 2022

IJMS

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Disturbances in the glutamatergic system have been increasingly documented in several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as from studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD. In addition, preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins. At present, there are no approved glutamatergic drugs for ASD, but several ongoing clinical trials are currently focusing on evaluating in autistic patients glutamatergic pharmaceuticals already approved for other conditions. In this review, we provide an overview of the literature concerning the role of glutamatergic neurotransmission in the pathophysiology of ASD and as a potential target for novel treatments.

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