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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.
Highlights
M-5MPEP and VU0424238 Decrease rapid eye movement (REM) Sleep Duration and Increase REM Sleep Latency The metabotropic glutamate receptor subtype 5 (mGlu5) partial negative allosteric modulators (NAMs) M-5MPEP did not affect wake durations when examined in 1 h bins across a 24 h period
When assessing REM sleep durations, there was a main effect of time of day but no main effect of dose or interaction following M-5MPEP administration when assessed in 1 h bins across the 24 h period (Figure 1G; for statistics, see Table 1)
Functional inhibition of mGlu5 represents a promising treatment approach for multiple disorders including depression, anxiety, substance use disorder and comorbid sleep disruptions, yet mitigating the risk of adverse effects remains a concern for clinical development (McGeehan and Olive, 2003; Busse et al, 2004; Dölen et al, 2007; Morin et al, 2010; Lindemann et al, 2015; Gould et al, 2018)
Summary
Functional antagonism of the metabotropic glutamate receptor subtype 5 (mGlu5) represents a promising target with broad therapeutic potential for the treatment of numerous disorders including fragile X syndrome (Yan et al, 2005; Dölen et al, 2007; for review see Nickols and Conn, 2014), Parkinson’s disease (Morin et al, 2010), anxiety (Busse et al, 2004; Swanson et al, 2005), depression (Lindemann et al, 2015), acute and neuropathic pain (Montana et al, 2009; Cavallone et al, 2020), and substance use disorder (McGeehan and Olive, 2003; Yararbas et al, 2010; Veeneman et al, 2011; Gould et al, 2015). In major depressive disorder (MDD), commonly reported sleep disturbances in patients include reductions in rapid eye movement (REM) sleep latency and increased REM duration/density (Armitage, 2007; Steiger and Pawlowski, 2019). Basimglurant, a full mGlu negative allosteric modulator (NAM), decreased REM duration and increased REM sleep latency (Lindemann et al, 2015), an EEG profile similar to several clinically prescribed antidepressants (Wichniak et al, 2017; Steiger and Pawlowski, 2019). Despite strong evidence for therapeutic potential of mGlu antagonism, an early human study reported dissociative-like effects in patients administered fenobam, introducing concerns surrounding the viability of this mechanism (Pecknold et al, 1982).
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