Diphenhydramine disrupts sleep architecture in 5XFAD Alzheimer's disease model and wild-type mice
5 affiliations
- 1Neurobiology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, 311 Research Drive, Durham, NC, 27710, USA
- 2DLH, LLC, 6720B Rockledge Drive, Suite 777, Bethesda, MD, 20817, USA
- 3Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, NC, 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, 116 Manning Drive, Chapel Hill, NC, 27599, USA; Carolina Institute for Developmental Disabilities, 101 Renee Lynne Court, Carrboro, NC, 27510, USA
- 4Neurobiology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, 311 Research Drive, Durham, NC, 27710, USA; The Department of Health & Kinesiology, The University of Texas at Austin, 2109 San Jacinto Blvd, Austin, TX, 78712, USA
- 5Neurobiology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, 311 Research Drive, Durham, NC, 27710, USA; Corresponding author.
Abstract
Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type female mice. Female 5XFAD (n = 16) and wild-type (WT) littermates (n = 14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG) and electromyography (EMG) continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD female mice had more time in NREM1 than WT female controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, and disrupted the light-dark distribution of sleep. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment resulted in NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model female mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.
Related
- Drosophila Appl loss disrupts proteins in mitochondrial oxidative and glycosylation pathways conserved in Alzheimer's disease
- Sleep Spindles and Slow Oscillations as Potential Biomarkers and Therapeutic Targets in Mild-to-Moderate Alzheimer's Disease.
- Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease
- Sex differences in sleep and memory relationships in older adults at risk for Alzheimer’s disease
- mTOR disrupts cerebrovascular RNA regulatory networks in Alzheimers disease
BibTeX
@article{copeland2026diphenhydramine,
title = {{Diphenhydramine disrupts sleep architecture in 5XFAD Alzheimer's disease model and wild-type mice}},
author = {Margaret H. Copeland and Diane E. Youngstrom and Kathryn S. Konrad and Graham H. Diering and Ayland C. Letsinger and Leslie R. Aksu and Jerrel L. Yakel and Jesse D. Cushman},
journal = {Neurobiology of Sleep and Circadian Rhythms},
year = {2026},
month = oct,
doi = {10.1016/j.nbscr.2026.100154},
url = {https://doi.org/10.1016/j.nbscr.2026.100154},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Diphenhydramine disrupts sleep architecture in 5XFAD Alzheimer's disease model and wild-type mice
AU - Margaret H. Copeland
AU - Diane E. Youngstrom
AU - Kathryn S. Konrad
AU - Graham H. Diering
AU - Ayland C. Letsinger
AU - Leslie R. Aksu
AU - Jerrel L. Yakel
AU - Jesse D. Cushman
PY - 2026
DA - 2026/10/16
JO - Neurobiology of Sleep and Circadian Rhythms
DO - 10.1016/j.nbscr.2026.100154
UR - https://doi.org/10.1016/j.nbscr.2026.100154
AB - Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type female mice. Female 5XFAD (n = 16) and wild-type (WT) littermates (n = 14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG) and electromyography (EMG) continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD female mice had more time in NREM1 than WT female controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, and disrupted the light-dark distribution of sleep. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment resulted in NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model female mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.
SN - 2451-9944
ER -