Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

Hikichi, Hirohiko; Kaku, Ayaka; Karasawa, Jun-ichi; Chaki, Shigeyuki

doi:10.1254/jphs.13036fp

Cited by 31 publications

(23 citation statements)

References 44 publications

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“…In the present study, TASP0443294 reversed methamphetamine-induced locomotor hyperactivity and improved MK-801-induced social memory impairment in rats. These results further support our previous findings and those of others that both mGlu2/3 receptor agonists and mGlu2 receptor positive allosteric modulators are effective in these models (9,11,19). However, some discrepancies exist among mGlu2 receptor positive allosteric modulators.…”

Section: Discussionsupporting

confidence: 92%

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Hikichi

Hiyoshi

Marumo

et al. 2015

Journal of Pharmacological Sciences

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Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.

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Section: Discussionsupporting

confidence: 92%

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Hikichi

Hiyoshi

Marumo

et al. 2015

Journal of Pharmacological Sciences

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“…As aforementioned, existing animal studies have shown that mGluR2/3 agonists can counteract the psychotic behavioral effects induced by PCP, ketamine and MK-801 (potent NMDA-R antagonists) treatment in rodents (Cartmell et al, 2000(Cartmell et al, , 1999Harich et al, 2007;Hikichi et al, 2013Hikichi et al, , 2010Imre et al, 2006;Moghaddam and Adams, 1998;Patil et al, 2007;Pitsikas and Markou, 2014;RorickKehn et al, 2007;Spooren et al, 2000). The therapeutic potential has however been shown to vary between different mGluR2/3 agonists, as some agonists failed to improve PCP-induced behavioral impairments (Schlumberger et al, 2009).…”

Section: The Mglur2/3 Agonist Ly379268 Restores Nmda-r and Gabaa-r Exmentioning

confidence: 99%

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

et al. 2016

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Rationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-daspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a twohit mouse model of schizophrenia. Methods Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. Disciplines Medicine and Health Sciences Publication DetailsEngel, M., Snikeris, P., Matosin, N., Newell, K. Anne., Huang, X. & Frank, E. (2016). mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. Psychopharmacology, 233 (8) AcknowledgmentsThis work was supported by the Schizophrenia Research Institute, utilising infrastructure funding from the NSW Ministry of Health. LY379268 was kindly gifted by Eli Lilly & Co (Indianapolis, USA). The funding bodies had no role in the study design, data collection and publication decisions. 2 AbstractRationale An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of Group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.Objectives We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.Me...

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“…BINA exhibited a more favourable PK profile, with improved plasma and brain exposures. BINA [42,43] remains the most attractive representative in the series and is, to date, one of the most extensively characterized mGlu2 receptor PAM compounds that has been used to predict antipsychotic and anxiolytic-like activity [43,[86][87][88][89].…”

Section: Indanonesmentioning

confidence: 99%

“…Interestingly, some examples in these patent applications are described (89,90) and Janssen (91)(92)(93) to be active in models predictive for antipsychotic activity. Finally, Bristol-Myers Squibb has very recently disclosed similar 1,2,4-triazolopyridines having secondary amines at the C 7 position leading to molecules with nanomolar activity in a cAMP biological assay, such as compound 98 (Fig.…”

Section: Triazolopyridinesmentioning

confidence: 99%

Metabotropic Glutamate Receptor 2 Activators

Cid¹,

Trabanco²,

Lavreysen

2014

Small Molecule Therapeutics for Schizophrenia

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Schizophrenia is a common and severe, often disabling psychiatric illness of unknown aetiology that affects approximately 24 million people worldwide. The illness is characterized by symptomatology comprising positive symptoms (hallucinations and delusional behaviours), negative symptoms (anhedonia, social withdrawal and apathy) and cognitive dysfunction (diminished capacity for learning, memory and executive function). Current pharmacological treatments are effective at alleviating positive symptoms but have limited impact on negative symptoms and cognitive deficits. Furthermore, the extrapyramidal symptoms, hyperprolactinemia and metabolic syndrome, including substantial weight gain, are typical side effects limiting the value of many of these drugs for patients. Thus, drugs that better serve the patient population by effectively treating all symptoms with improved safety and tolerability remain a critical unmet need. Modulation of the metabotropic glutamate type 2 (mGlu2) receptor has emerged as a promising mechanism for the treatment of CNS diseases, with the potential to provide a new and more effective avenue for the treatment of schizophrenia.

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Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

Cited by 31 publications

References 44 publications

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

Metabotropic Glutamate Receptor 2 Activators

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