Positive allosteric modulation of mGlu7 receptors by AMN082 affects sleep and wakefulness in the rat

Evidence indicates that metabotropic glutamate receptors (mGlu) are involved in the regulation of physiological and behavioral processes, and glutamate has been implicated in several pathologies of the Central Nervous System. Pharmacological evidence suggests the therapeutic potential of targeting mGlu7 receptor in a number of pathological conditions; and previous research has shown the involvement of glutamate on sleep and wakefulness regulation. Here, the effects of mGlu7 receptor selective modulation on sleep and wake states are explored. 32 male Wistar rats were implanted with electrodes for recording sleep and wakefulness. N,N′-Bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) (5, 10, and 20 mg/kg, i.p.), a potent, selective and systemically active mGlu7 receptor positive allosteric modulator, or vehicle was administered 1 hour after the beginning of the light period. AMN082 (5 and 10 mg/kg) significantly increased total time of sleep; and time spent on Slow Wave Sleep (SWS) was increased. AMN082 at 10 mg/kg specifically affected Light SWS, increasing time spent on Light SWS. The highest dose of AMN082, 20 mg/kg, significantly reduced time spent in Rapid Eye Movement (REM) sleep, decreasing the number of REM sleep episodes and their mean duration. Total time spent awake was increased and mean episode duration of wakefulness was prolonged. The present results suggest that mGlu7 receptors might be involved in sleep regulation and drugs targeting these receptors could affect sleep and wakefulness architecture.

► The role of mGlu7 receptor on sleep and wakefulness was analyzed in rats. ► Positive modulation of mGlu7 by AMN082 showed biphasic effects. ► Low and intermediate doses increased NREM sleep and decreased wake. ► The highest dose suppressed REM sleep and increased wakefulness. ► Drugs targeting mGlu7 receptors should consider their effects on sleep architecture.