Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and d-amphetamine models of schizophrenia

Profaci, Caterina P.; Krolikowski, Kristyn A.; Olszewski, Rafal T.; Neale, Joseph H.

doi:10.1007/s00213-011-2200-0

Cited by 22 publications

(13 citation statements)

References 61 publications

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“…mGlu 2/3 R agonists reduce both glutamate release and schizophrenia-like behaviors in animal models, although the effects on NMDA antagonist-induced disruptions in PPI is inconsistent (Imre et al, 2006; Galici et al, 2005; Henry et al, 2002). Further, N -acetylaspartylglutamate peptidase inhibitors ZJ43 and 2-PMPA suppress glutamate release but failed to reverse phencyclidine-induced PPI deficits (Profaci et al, 2011). These data indicate that modulation of glutamate tone does not consistently affect PPI disruptions induced by NMDA receptor blockade.…”

Section: Discussionmentioning

confidence: 99%

The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice

et al. 2012

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Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a “Low” or “High” gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the “low gating” group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.

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Section: Discussionmentioning

confidence: 99%

The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice

et al. 2012

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“…The neurotransmitter glutamate plays a key role in modulation of PPI that has been found impaired in patients with schizophrenia [191][192][193][194][195]. One study evaluated PPI in patients with DS and NDS, reporting PPI deficit and reduced facilitation in the later phase of prepulse condition in DS patients and an impairment in the earlier phase of prepulse condition in NDS patients [196].…”

Section: Studies Of Associations Between Glutamate and Ds And Ndsmentioning

confidence: 99%

Neurobiological background of negative symptoms

Galderisi

Merlotti

Mucci

2015

Eur Arch Psychiatry Clin Neurosci

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Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords "negative symptoms," "deficit schizophrenia," "persistent negative symptoms," "neurotransmissions," "neuroimaging" and "genetic." Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms.

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“…In the PCP model, mGluR2/3 agonists (e.g., LY379268, LY354740, LY544344) were reported to effectively reverse certain behavioral phenotypes such as locomotor activity and prepulse inhibition (Cartmell et al, 2000a, Profaci et al, 2011, Rorick-Kehn et al, 2006, Swanson and Schoepp, 2002). LY379268 also resulted in a significant reduction in ketamine-induced hyperactivity (Imre et al, 2006, Lorrain et al, 2003b) and MK-801-induced hyperlocomotion (Chartoff et al, 2005, Xi, Li, 2011).…”

Section: In Vivo Studies Of Mglur2/3 Agonists In Animal Models Of Szmentioning

confidence: 99%

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists’ mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2.

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Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and d-amphetamine models of schizophrenia

Cited by 22 publications

References 61 publications

The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice

The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice

Neurobiological background of negative symptoms

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

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