Partial mGlu₅ Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without...

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.