Enduring NREM sleep fragmentation following methotrexate chemotherapy in cancer-naïve mice.

Abstract

Study objectives: Sleep disruption is common in people with cancer and survivors, but understanding the mechanisms driving these problems is difficult due to heterogeneity among cancers, patients, and treatment modalities. We investigated whether the common antifolate chemotherapeutic agent methotrexate (MTX) promotes changes in sleep independent of cancer in adult mice.

Methods: Adult mice (> 7 weeks old, both sexes, n=13) were exposed to either a clinically relevant chemotherapy regimen with methotrexate (n=7) or saline (control, n=6) accompanied by continuous EEG/EMG telemetry recording. Sleep states were scored as either wake, NREM sleep, or REM sleep in 5-second epochs weekly during MTX or saline treatment and then two weeks following the last injection to examine enduring changes in sleep/wake cycles.

Results: MTX exposure caused NREM sleep fragmentation, indicated by (1) shorter and more frequent NREM sleep bouts, (2) more transitions between wake & NREM sleep, and (3) more accumulated NREM sleep bouts over time. These effects were first detected after the second MTX injection and lasted into the two-week follow-up recording. MTX did not alter delta power in NREM sleep, indicating no changes to sleep quality. The total time spent in each vigilance state remained unaffected by MTX use. Finally, when given MTX, male mice displayed more fragmented sleep compared to female mice.

Conclusions: Methotrexate promotes NREM sleep fragmentation, without affecting sleep quality or time spent asleep. This effect is stronger in males. These data suggest that chemotherapy can cause long-term sleep disruption independent of cancer presence.