Wake-Promoting and EEG Spectral Effects of Modafinil After Acute or Chronic Administration in the R6/2 Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.

Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning

“…S6B, C). In humans, increased delta power and decreased theta power during wake has been correlated with subjective feelings of sleepiness [55,56], and in mice the wake-promoting drug modafinil decreases delta power and increases theta power during wakefulness [57,58]. Taken together, the observed decreased delta and increased theta power, which are signatures of lower sleep pressure, suggest increased wakefulness in the aged Bmal1 cKO mice.…”

Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning

“…S6 B-C ). In humans, increased delta power and decreased theta power during wake has been correlated with subjective feelings of sleepiness (Bylsma et al, 1994; Painold et al, 2010), and in mice the wake-promoting drug modafinil decreases delta power and increases theta power during wakefulness (Willie et al, 2005; Vas et al, 2020). Taken together, the observed decreased delta and increased theta power, which are signatures of lower sleep pressure, suggests increased wakefulness in the aged Bmal1 cKO mice.…”

Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington’s Disease

“…There is both indirect [18] and direct [78][79][80] evidence that cognitive deficits and circadian dysfunction are linked. Pharmacological imposition of sleep and wakefulness using alprazolam and modafinil markedly improved cognitive performance in a two-choice visual discrimination task in the R6/2 line of transgenic HD mice [78,79] and reversed some EEG spectral changes [81]. Treatment with the orexin receptor antagonist suvorexant was found to alleviate cognitive deficits in R6/1 mice [80].…”