Partial mGlu5 Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without Affecting Cognition or Quantitative EEG

Abstract

Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu5) demonstrate anxiolytic-like and antidepressant-like effects yet concern regarding adverse effect liability remains. Functional coupling of mGlu5 with ionotropic N-methyl-D-aspartate receptors (NMDARs) represents a potential mechanism through which full inhibition leads to adverse effects, as NMDAR inhibition can induce cognitive impairments and psychotomimetic-like effects. Recent development of “partial” mGlu5 NAMs, characterized by submaximal but saturable levels of blockade, may represent a novel development approach to broaden the therapeutic index of mGlu5 NAMs. This study compared the partial mGlu5 NAM, M-5MPEP, with the full mGlu5 NAM, VU0424238 on sleep, cognition, and brain function alone and in combination with a subthreshold dose of the NMDAR antagonist, MK-801, using a paired-associates learning (PAL) cognition task and electroencephalography (EEG) in rats. M-5MPEP and VU0424238 decreased rapid eye movement (REM) sleep and increased REM sleep latency, both putative biomarkers of antidepressant-like activity. Neither compound alone affected accuracy, but 30 mg/kg VU0424238 combined with MK-801 decreased accuracy on the PAL task. Using quantitative EEG, VU0424238, but not M-5MPEP, prolonged arousal-related elevations in high gamma power, and, in combination, VU0424238 potentiated effects of MK-801 on high gamma power. Together, these studies further support a functional interaction between mGlu5 and NMDARs that may correspond with cognitive impairments. Present data support further development of partial mGlu5 NAMs given their potentially broader therapeutic index than full mGlu5 NAMs and use of EEG as a translational biomarker to titrate doses aligning with therapeutic versus adverse effects.

Use of Quantitative Electroencephalography to Inform Age- and Sex-Related Differences in NMDA Receptor Function Following MK-801 Administration

“…Aberrant elevations in resting-state gamma power have been identified in patients with schizophrenia and correspond to positive symptoms and cognitive impairment [ 22 , 23 , 24 , 25 ]. Importantly, gamma power is directly impacted by changes in NMDA receptor function, and NMDA receptor antagonists including MK-801 increase gamma power and disrupt cognition [ 30 , 34 ]. Although sex- and age-related differences are relevant factors influencing the pathophysiology of schizophrenia, how these variables affect NMDA receptor function has been largely overlooked in preclinical studies as well as in clinical trials [ 35 ].…”

“…Rats were anesthetized with isoflurane (3–5% induction, 1–3% maintenance) and implanted with a subcutaneous transmitter (HD-S02; Data Sciences International [DSI], Minneapolis, MN, USA) as previously described [ 34 , 85 ]. In brief, transmitters were implanted subcutaneously near the dorsal flank, and four wires were tunneled towards the skull.…”

“…Ten-second epochs were manually designated as different sleep/wake stages based on accepted oscillatory patterns (wake, rapid eye movement [REM], non-REM [NREM]) or artifact using Neuroscore 3.0 Software (DSI) as previously described [ 34 , 85 ]. Artifact was characterized by abnormally high amplitude or signal dropout.…”

The Metabotropic Glutamate 5 Receptor in Sleep and Wakefulness: Focus on the Cortico-Thalamo-Cortical Oscillations

“…Both the slow and delta oscillations arise from variations in the resting membrane potentials of both thalamic and cortical neurons [ 74 , 75 ]. These reciprocally interconnected cells can switch between depolarized, the so called ‘UP’ state, and hyperpolarized, the ‘DOWN’ state.…”

“…In the last decade, there have been enormous efforts in developing specific mGlu5 receptor allosteric modulators, positive and negative allosteric modulators (PAMs and NAMs), which bind to sites found in the 7-TM domain of the receptor. Allosteric ligands of the mGlu5 receptor remain an attractive therapeutic strategy for different neurological and psychiatric disorders and comorbid sleep disturbances [ 75 ].…”