Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Abstract

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.

• Authors: Jerri M Rook, Zixiu Xiang, Xiaohui Lv, Ayan Ghoshal, Jonathan W Dickerson, Thomas M Bridges, Kari A Johnson, Daniel J Foster, Karen J Gregory, Paige N Vinson, Analisa D Thompson, Nellie Byun, Rebekah L Collier, Michael Bubser, Michael T Nedelcovych, Robert W Gould, Shaun R Stauffer, J Scott Daniels, Colleen M Niswender, Hilde Lavreysen, Claire Mackie, Susana Conde-Ceide, Jesus Alcazar, José M Bartolomé-Nebreda, Gregor J Macdonald, John C Talpos, Thomas Steckler, Carrie K Jones, Craig W Lindsley, P Jeffrey Conn
• Journal: Neuron (Neuron) Vol. 86 Issue 4 Pg. 1029-1040 (May 20 2015) ISSN: 1097-4199 [Electronic] United States
• PMID: 25937172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• Receptor, Metabotropic Glutamate 5
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid

Topics

• Allosteric Regulation (drug effects)
• Animals
• Antipsychotic Agents (pharmacology)
• Cognition (drug effects, physiology)
• Glutamic Acid (metabolism)
• HEK293 Cells
• Hippocampus (drug effects, physiology)
• Humans
• Male
• Rats, Sprague-Dawley
• Receptor, Metabotropic Glutamate 5 (genetics, metabolism)
• Receptors, N-Methyl-D-Aspartate (physiology)
• Signal Transduction (drug effects)