Pharmacological Modulation of Sleep Homeostasis in Rat: Novel Effects of an mGluR2/3 Antagonist

Abstract

Increasing vigilance without incurring the negative consequences of extended wakefulness such as daytime sleepiness and cognitive impairment is a major challenge in treating many sleep disorders. The present work compares two closely related mGluR2/3 antagonists LY3020371 and LY341495 with two well-known wake-promoting compounds caffeine and d-amphetamine. Sleep homeostasis properties were explored in male Wistar rats by manipulating levels of wakefulness via (1) physiological sleep restriction (SR), (2) pharmacological action, or (3) a combination of these. A two-phase nonlinear mixed-effects model combining a quadratic and exponential function at an empirically estimated join point allowed the quantification of wake-promoting properties and any subsequent sleep rebound. A simple response latency task (SRLT) following SR assessed functional capacity of sleep-restricted animals treated with our test compounds. Caffeine and d-amphetamine increased wakefulness with a subsequent full recovery of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and were unable to fully reverse SR-induced impairments in SRLT. In contrast, LY3020371 increased wakefulness with no subsequent elevation of NREM sleep, delta power, delta energy, or sleep bout length and count, yet REM sleep recovered above baseline levels. Prior sleep pressure obtained using an SR protocol had no impact on the wake-promoting effect of LY3020371 and NREM sleep rebound remained blocked. Furthermore, LY341495 increased functional capacity across SRLT measures following SR. These results establish the critical role of glutamate in sleep homeostasis and support the existence of independent mechanisms for NREM and REM sleep homeostasis.

The role of ultradian rhythms in post-deprivation rebounds and diurnal rhythms of sleep and wakefulness in rats

“…By contrast, in the present study the group mean rebounds were essentially complete for REM sleep (Fig 6), also corroborating several previous reports for rats in an LD cycle [5,17,47,60]. This suggests that the REM response differs to some degree from that of NREM in terms of its underlying mechanism.…”

The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers

“…However, there was some gradual recovery of lost sleep throughout the dark period at the highest doses. The lack of a rebound increase in sleep after extended waking is similar to what is reported for modafinil (Edgar and Seidel, 1997) but different from what is observed with traditional stimulants like d-amphetamine (Hanley et al, 2019). The duration of the wake-promoting effects also paralleled increases in locomotor activity (data not shown).…”

“…In the first sleep study, the home cage is the recording cage (Hanley et al, 2019). Each animal was housed individually within a specially modified Ancare™ microisolator cage having a custom polycarbonate filter-top riser and a custom ultra-low-torque slip-ring commutator (Hypnion, Inc.) on a 12-hour light/dark cycle with free access to standard animal laboratory food and water.…”

Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration

“…The SCORE2004™ bioassay facilitated the acquisition of multiple concomitant physiological measurements from 30 animals simultaneously. Validation of the SCORE2004™ technology has been previously described [ 36 – 38 ]. EEG signals, recorded as the differential between front and back contralateral skull screws, were amplified 10,000×, bandpass filtered at 1–300 Hz and digitised at 400 Hz (Grass Corp., Quincy, MA, USA).…”