Off-target potential of AMN082 on sleep EEG and related physiological variables: Evidence from mGluR7 (-/-) mice

Abstract

The metabotropic glutamate receptor type 7 (mGluR7), a most abundant presynaptic G protein-coupled receptor in the brain provides an attractive mechanism to fast fine-tune abnormal excitatory neurotransmission and synaptic plasticity associated with emotional and cognitive impairments in neuropsychiatric and neurodegenerative disorders. Preclinical studies using AMN082, the mGluR7 allosteric agonist, produced conflicting results, so that results of further in-vivo studies are needed. Here, we investigated effects of subcutaneous administration at the lights onset of AMN082 on sleep-wake architecture and spectral contents in rats. In an attempt to solve the reported mixed results, we estimated the specific functional effects in mGluR7 (-/-) mice and their wild type (WT) littermates. In rats, AMN082 (2.5mg/kg) elicited a primary waking effect over the first 2h post-administration by consistent increases in the number of waking bouts and transitions from sleep states towards wakefulness. In mice, baseline recordings over 72h showed comparable spontaneous sleep-wake cycle in mGluR7 (-/-) mice and their WT littermates, suggesting that mGluR7 is not involved in the regulation of vigilance states. Remarkably, cortical arousal properties of AMN082 were confirmed in WT mice, and occurred concomitantly with a marked decrease in body temperature, likely dissociated from locomotor activity. Surprisingly, the wake arousal and hypothermia effects of AMN082 were also observed in mGluR7 (-/-) mice. AMN082 significantly attenuated the slow wave activity during sleep and had no effect on waking EEG power in the 4-50Hz range. The present findings in rats do not lend support to proposed somnogenic effects of AMN082, while comparable responses in WT and mGluR7 (-/-) mice provide further evidence of an off-target action of AMN082 that contributes to its waking properties.

Keywords: AMN082; Body temperature; EEG oscillations; Glutamate; Locomotor activity; Off-target; Psychiatric and neurodegenerative disorders; Rats; Sleep-wake cycle; mGluR7; mGluR7 (−/−) mice.