Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

Krystal, John H.; Abi-Saab, Walid; Perry, Edward; D’Souza, Deepak Cyril; Liu, Nianjin; Gueorguieva, Ralitza; McDougall, Lisa; Hunsberger, Tracy; Belger, Ayşenil; Levine, Louise R.; Breier, Alan

doi:10.1007/s00213-004-1982-8

Cited by 256 publications

(185 citation statements)

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“…Consistent with this, LY354740 has been shown to inhibit increases in glutamate induced by the depolarizing agent veratridine in the striatum of freely moving rats (Battaglia et al, 1997), and reduce the response to electrically evoked glutamate release in a manner consistent with a presynaptic site of action (Capogna, 2004;Kilbride et al, 1998). Agonists of mGluR2/3 such as LY354740 can antagonize the behavioral and neurochemical effects of PCP in rodents (Lorrain et al, 2003;Cartmell et al, 1999;Moghaddam and Adams, 1998) and produce a dosedependent suppression of ketamine-induced impairment of working memory by ketamine in human volunteers (Krystal et al, 2005). Our results show a significant inhibition of the amplitude of the response to PCP in most of the activated regions, an effect that parallels the preclinical and clinical findings mentioned above.…”

Section: Effect Of Ly354740mentioning

confidence: 99%

“…As the effect of NMDAR antagonists is thought to involve a dysregulation of glutamatergic neurotransmission (Farber, 2003), we assessed the effect of two drugs that have been suggested to prevent aberrant glutamatergic activity through distinct pharmacological mechanisms: the metabotropic glutamate 2/3 (mGluR2/3) receptor agonist LY354740 and the brain sodium channel blocker lamotrigine. LY354740 has been shown to prevent PCP-induced glutamate release , and to block dose-dependently the behavioral effects of NMDAR antagonists in rodents (Schoepp and Marek, 2002) and in human volunteers (Krystal et al, 2005). Lamotrigine (lamictal, Messenheimer, 1995) is a broad-spectrum anticonvulsant that reduces neuronal excitability and glutamatergic transmission , and that has been shown to prevent psychotic symptoms and disruption of behavior induced by ketamine or PCP in rodents and human volunteers (Idris et al, 2005;Brody et al, 2003;Anand et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

Neuropsychopharmacol

109

118

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Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D 2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D 2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.

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Section: Effect Of Ly354740mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

Neuropsychopharmacol

109

118

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“…Mechanistically, it has been proposed that GRM2/3 agonists reverse the cortical glutamate efflux that is induced by NMDA antagonist administration, and which has been linked to the cognitive dysfunction. Furthermore, there is preliminary evidence in humans that group II agonists are effective in improving cognitive deficits induced by ketamine (Krystal et al, 2005) and that they possess antipsychotic activity (Patil et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

Sartorius

Weinberger

Hyde

et al. 2008

Neuropsychopharmacol

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Genetic variation in the metabotropic glutamate receptor 3 (GRM3, mGluR3) has been associated with schizophrenia, but the mechanism by which it confers risk is unknown. Previously, we reported the existence of a splice variant, GRM3D4, which has an exon 4 deletion and encodes a truncated form of the receptor that is expressed in brain. The aim of the present study was to determine whether expression of this splice variant is altered in individuals with schizophrenia and is affected by a risk genotype. We measured GRM3 and GRM3D4 transcripts in human dorsolateral prefrontal cortex (DLPFC) and hippocampus of the CBDB/NIMH collection (B70 controls, B30 schizophrenia patients) and in the DLPFC of the Stanley Array Collection. Expression data of GRM3 mRNA in the DLPFC were inconsistent: GRM3 was increased in schizophrenia patients in the CBDB/NIMH collection, but not in the Stanley Array Collection. GRM3 expression did not change in the frontal cortex of rats treated chronically with haloperidol or clozapine. An exon 3 SNP previously associated with schizophrenia (rs2228595) predicted increased expression of the GRM3D4 splice variant. Our results suggest that rs2228595, or a neighboring SNP in linkage disequilibrium with it, may contribute to risk for schizophrenia by modulating GRM3 splicing.

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“…Agonist activation of mGluR2/3 reduces release of glutamate and GABA, as well as reversing the effects of psychomimetics in both rodents and humans (Hashimoto et al, 2013;Imre, 2007;Krystal et al, 2005;Spooren et al, 2003). Several clinical, preclinical and in vitro studies have explored the consequences of mGluR2/3 endogenous and exogenous activation; however, the therapeutic suitability of mGluR2/3 agonists remains unclear.…”

Section: Introductionmentioning

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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Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

Abstract: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Cited by 256 publications

References 37 publications

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

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

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