Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats

Abstract

Rationale: Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved in neuronal plasticity, and disturbance in vigilance states and cortical network connectivity contribute significantly to cognitive deficits described in schizophrenia and Alzheimer's disease. Here, we examined the circadian changes of mGluR5 density and the functional response to modulation of mGluR5 signaling.

Methods: The current study carried out in Sprague-Dawley rats quantified the density of mGluR5 across the light-dark cycle with autoradiography. The central activity of mGluR5 negative allosteric modulators (2-methyl-6-(phenylethynyl)pyridine (MPEP) and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and positive allosteric modulators (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone (ADX47273) and (7S)-3-tert-butyl-7-[3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (LSN2814617) was examined on sleep-wake architecture. The functional effect of mGluR5 modulation on cortical networks communication was described in freely moving animals.

Results: The density of mGluR5 in the striatal, cortical, hippocampal and thalamic structures was unchanged across the light-dark cycle. Allosteric blockade of mGluR5 consistently consolidated deep sleep, enhanced sleep efficiency and elicited prominent functional coherent network activity in slow theta and gamma oscillations. However, allosteric activation of mGluR5 increased waking, decreased deep sleep and reduced functional network connectivity following the activation of slow alpha oscillatory activity.

Conclusion: This functional study differentiates the pharmacology of allosteric blockade of mGluR5 from that of allosteric activation and suggests that mGluR5 blockade enhances sleep and facilitates oscillatory network connectivity, both processes being known to have relevance in cognition processes.