Negative allosteric modulator of the metabotropic glutamate receptor 7 (mGlu7) ADX71743 increases wakefulness, reduces sleep and alters stress-induced changes in the brain neurotransmitter levels

Objective Converging evidence suggests that metabotropic glutamate receptor 7 (mGlu7) contributes to sleep–wake regulation and stress reactivity. We used the selective negative allosteric modulator (NAM) ADX71743 to examine the role of mGlu7 in sleep–wake control and in basal and stress-evoked neurotransmitter release in freely moving rats. Method Rats were implanted with electrodes and telemetry devices to record electroencephalogram (EEG), neck muscle electromyogram (EMG), motor activity (MA), and body temperature (BT) at baseline and for 9 h after subcutaneous (sc) administration of ADX71743 (50, 100, or 150 mg/kg) or vehicle (50% cyclodextrin in water), given 2 h after lights on. In a separate cohort, rats were implanted with microdialysis probes in the prefrontal cortex (PFC) and ventral hippocampus (vHipp). Samples were collected at baseline, followed by sc ADX71743 (100 mg/kg) or vehicle and 10 min of light handling 60 min later. Extracellular glutamate (Glu), GABA, glycine (Gly), serotonin (5-HT), norepinephrine (NE), and dopamine (DA) were quantified over the 180 min sampling period. Results ADX71743 increased wakefulness by up to 100% and reduced rapid-eye-movement (REM) sleep by up to 100% and non-REM (NREM) sleep by up to 75% (all p<0.05), with comparable effects across doses. ADX71743 also delayed NREM and REM sleep onset by nearly 2-fold (p<0.05) for 2 h after dosing, without altering MA or BT. Basal neurotransmitter concentrations were unchanged. However, ADX71743 attenuated stress-related changes in GABA and 5-HT, maintaining higher levels in the vHipp than in vehicle-treated controls. Stress-evoked NE and DA increases tended to be greater after ADX71743 than after vehicle. Neither treatment nor stress markedly affected Glu or Gly in the PFC or vHipp. Conclusions These findings support an important role for mGlu7 in regulating sleep and wakefulness. The ADX71743-associated maintenance of higher vHipp 5-HT and GABA levels after stress may contribute to reduced stress- and anxiety-like reactivity produced by mGlu7 inhibition.