title: The mGlu₅ positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat.
abstract: Metabotropic glutamate 5 (mGlu₅) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu₅ positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu₅ PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu₅ and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu₅ receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors.affiliation: Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, Surrey, UK. gastambidefr@lilly.com
authors.forename: Francois
authors.initials: F
authors.lastname: Gastambide
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.forename: Mark D
authors.initials: MD
authors.lastname: Tricklebank
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004193:Discrimination Learning / Q000187:drug effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists; D008297:Male; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D018697:Nootropic Agents / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000209:etiology / Q000517:prevention & control*; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C576176:N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide; D018697:Nootropic Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate