Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat

Imre, Gábor; Salomons, Amber R.; Jongsma, Minke E.; Fokkema, Dirk S.; Boer, Johan A. den; Horst, Gert J. Ter

doi:10.1016/j.pbb.2006.05.021

Cited by 58 publications

(61 citation statements)

References 37 publications

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“…Although the present findings do not allow predictions about clinical efficacy of LY379268, it is worth noting that the better assimilated analog LY404039 ameliorates both positive and negative symptoms in schizophrenia patients (Patil et al, 2007;Harrison, 2008). Some studies reported that LY379268 failed to block PPI alterations (but not other behavioral abnormalities) induced by administration of NMDA antagonists (Cartmell et al, 1999(Cartmell et al, , 2000Clark et al, 2002;Imre et al, 2006). The different results may be explained by the different paradigms used to impair PPI; indeed, it is conceivable that the reduction in glutamatergic transmission induced by NMDA antagonism is more intense than that induced by the upregulation of GLT-1, and that the modulating effect of LY379268 on glutamatergic transmission is not sufficient to restore PPI induced by NMDA antagonists.…”

Section: Ly379268 Blocks Cef-induced Ppi Impairment M Bellesi and F Cmentioning

confidence: 62%

“…In this paper, we showed that LY379268, a compound effective in animal models of schizophrenia (Cartmell et al, 1999(Cartmell et al, , 2000Clark et al, 2002;Imre et al, 2006;Imre, 2007), blocked PPI impairment associated with GLT-1 upregulation. Although the present findings do not allow predictions about clinical efficacy of LY379268, it is worth noting that the better assimilated analog LY404039 ameliorates both positive and negative symptoms in schizophrenia patients (Patil et al, 2007;Harrison, 2008).…”

Section: Ly379268 Blocks Cef-induced Ppi Impairment M Bellesi and F Cmentioning

confidence: 81%

“…The selective mGluR2/3 agonist LY379268 attenuates behavioral abnormalities in animal models of schizophrenia, and its analog LY404039 is effective in a schizophrenia phase 2 clinical trial (Cartmell et al, 1999(Cartmell et al, , 2000Clark et al, 2002;Imre et al, 2006;Imre, 2007;Patil et al, 2007;Harrison, 2008). Recently, we have shown that ceftriaxone (CEF)-induced GLT-1 upregulation impairs hippocampal long-term depression (LTD) in a DHK-reversible manner by limiting activation of mGluR2/3, thus indicating that a reduced function of mGluR2/3 mediates the effects of GLT-1 upregulation (Omrani et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Bellesi

Conti

2010

Neuropsychopharmacol

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The main glutamate transporter GLT-1 is responsible for clearing synaptically released glutamate from the extracellular space and contributes to the shaping of glutamatergic transmission. Recently, it has been shown that ceftriaxone (CEF)-induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a simple form of information processing that is reduced in schizophrenia, and determines a strong reduction in hippocampal metabotropic glutamate receptor (mGluR)2/3-dependent long-term depression. In this study, we tested the hypothesis that administration of the mGluR2/3 agonist LY379268 blocks the effect of GLT-1 upregulation on PPI of the startle. We showed that administration of LY379268 (1 mg/kg) prevented PPI alterations associated with GLT-1 upregulation, suggesting that CEF-induced PPI impairment was mGluR2/3 dependent. In addition, we showed that CEF-induced GLT-1 upregulaton did not alter the expression of mGluR2/3, and also that it occurred at sites of mGluR2/3 expression. These results indicate a novel mechanism by which GLT-1 upregulation modulates PPI of the startle.

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Section: Ly379268 Blocks Cef-induced Ppi Impairment M Bellesi and F Cmentioning

confidence: 62%

Section: Ly379268 Blocks Cef-induced Ppi Impairment M Bellesi and F Cmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Bellesi

Conti

2010

Neuropsychopharmacol

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“…Given its similarity to D2 antagonists in a range of neurochemical and behavioral models, the failure of TP-10 to affect PPI was an unexpected observation. In weighing this observation, it is worth noting that mGluR2/3 agonists have also been reported to be inactive against the disruption of PPI by NMDA antagonists (Henry et al, 2002;Imre et al, 2006), yet results from a recent phase II study of the mGluR2/3 agonist prodrug, LY2140023, report antipsychotic efficacy comparable with olanzapine (Patil et al, 2007). Catalepsy is thought to reflect drug-induced suppression of the ability to initiate a behavioral response and is considered to be predictive of extrapyramidal side effects (Hoffman and Donovan, 1995).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia

Schmidt

Chapin²,

Cianfrogna³

et al. 2008

J Pharmacol Exp Ther

268

298

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We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8: 54 -59, 2007 386 -396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

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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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Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat

Cited by 58 publications

References 37 publications

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia

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

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