The MGluR2 Positive Allosteric Modulator, SAR218645, Improves Memory and Attention Deficits in Translational Models of Cognitive Symptoms Associated with Schizophrenia

Overview

Journal Sci Rep

Specialty Science

Date 2016 Oct 14

PMID 27734956

Citations 26

Authors

Guy Griebel

Philippe Pichat

Denis Boulay

Vanessa Naimoli

Lisa Potestio

Robert Featherstone

Sukhveen Sahni

Henry Defex

Christophe Desvignes

Franck Slowinski

Xavier Vige

Olivier E Bergis

Rosy Sher

Raymond Kosley

Sathapana Kongsamut

Mark D Black

Geoffrey B Varty

Affiliations

Soon will be listed here.

Abstract

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγS binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1 mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.

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References

Broadbent N, Squire L, Clark R . Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci U S A. 2004; 101(40):14515-20. PMC: 521976. DOI: 10.1073/pnas.0406344101. View

Schoepp D, Johnson B, Wright R, Salhoff C, Mayne N, Wu S . LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology. 1997; 36(1):1-11. DOI: 10.1016/s0028-3908(96)00160-8. View

Lijffijt M, Lane S, Meier S, Boutros N, Burroughs S, Steinberg J . P50, N100, and P200 sensory gating: relationships with behavioral inhibition, attention, and working memory. Psychophysiology. 2009; 46(5):1059-68. PMC: 2821570. DOI: 10.1111/j.1469-8986.2009.00845.x. View

Ennaceur A, Delacour J . A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988; 31(1):47-59. DOI: 10.1016/0166-4328(88)90157-x. View

Duncan G, Moy S, Lieberman J, Koller B . Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction. Pharmacol Biochem Behav. 2006; 85(3):481-91. PMC: 1861823. DOI: 10.1016/j.pbb.2006.09.017. View

Freedman R . Schizophrenia. N Engl J Med. 2003; 349(18):1738-49. DOI: 10.1056/NEJMra035458. View

Yokoi M, Kobayashi K, Manabe T, Takahashi T, Sakaguchi I, Katsuura G . Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science. 1996; 273(5275):645-7. DOI: 10.1126/science.273.5275.645. View

Vlcek P, Bob P, Raboch J . Sensory disturbances, inhibitory deficits, and the P50 wave in schizophrenia. Neuropsychiatr Dis Treat. 2014; 10:1309-15. PMC: 4106969. DOI: 10.2147/NDT.S64219. View

Hiyoshi T, Hikichi H, Karasawa J, Chaki S . Metabotropic glutamate receptors regulate cortical gamma hyperactivities elicited by ketamine in rats. Neurosci Lett. 2014; 567:30-4. DOI: 10.1016/j.neulet.2014.03.025. View

10.

Weiner I . The "two-headed" latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment. Psychopharmacology (Berl). 2003; 169(3-4):257-97. DOI: 10.1007/s00213-002-1313-x. View

11.

Moghaddam B, Adams B . Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998; 281(5381):1349-52. DOI: 10.1126/science.281.5381.1349. View

12.

DallOlio R, Gaggi R, Bonfante V, Gandolfi O . The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function. Behav Pharmacol. 2000; 10(1):63-71. DOI: 10.1097/00008877-199902000-00006. View

13.

de Bruin N, Ellenbroek B, Cools A, Coenen A, van Luijtelaar E . Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats. Psychopharmacology (Berl). 1999; 142(1):9-17. DOI: 10.1007/s002130050856. View

14.

Galici R, Jones C, Hemstapat K, Nong Y, Echemendia N, Williams L . Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther. 2006; 318(1):173-85. DOI: 10.1124/jpet.106.102046. View

15.

Johnson M, Adler L . Transient impairment in P50 auditory sensory gating induced by a cold-pressor test. Biol Psychiatry. 1993; 33(5):380-7. DOI: 10.1016/0006-3223(93)90328-b. View

16.

Smucny J, Stevens K, Olincy A, Tregellas J . Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation. Transl Psychiatry. 2015; 5:e587. PMC: 4490287. DOI: 10.1038/tp.2015.77. View

17.

BERT L, Robert F, Denoroy L, Stoppini L, Renaud B . Enhanced temporal resolution for the microdialysis monitoring of catecholamines and excitatory amino acids using capillary electrophoresis with laser-induced fluorescence detection. Analytical developments and in vitro validations. J Chromatogr A. 1996; 755(1):99-111. DOI: 10.1016/s0021-9673(96)00595-x. View

18.

Kovacic P, Somanathan R . Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity. Oxid Med Cell Longev. 2010; 3(1):13-22. PMC: 2835885. DOI: 10.4161/oxim.3.1.10028. View

19.

Cullum C, Harris J, Waldo M, Smernoff E, Madison A, Nagamoto H . Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia. Schizophr Res. 1993; 10(2):131-41. DOI: 10.1016/0920-9964(93)90048-n. View

20.

Moghaddam B, Javitt D . From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2011; 37(1):4-15. PMC: 3238069. DOI: 10.1038/npp.2011.181. View