The Neurochemical Basis of High-Altitude Sleep Disruption: Disentangling Respiratory and Sleep-Circuit Mechanisms Toward Targeted Pharmacotherapy.

Authors

Yue Dong, Zhihao Zou, Qinghai Shi

Published in

Current neuropharmacology. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

High-altitude sleep disruption is a complex syndrome that many lowlanders experience when they reach plateaus above 2,500 meters, characterized by frequent awakenings, reduced slow-wave sleep, nocturnal hypoxemia, and central sleep apnea related to unstable ventilation. A prevailing assumption in high-altitude sleep medicine holds that stabilising ventilation, chiefly via acetazolamide, is sufficient to restore sleep quality. This assumption is challenged by a randomised controlled trial demonstrating that acetazolamide significantly reduced the apnoea-hypopnoea index (AHI) and improved oxygenation at 3,100 m while failing to restore N3 slow-wave sleep fraction, total sleep time, or sleep efficiency, parameters that remained impaired in both drug and placebo groups. This dissociation between respiratory and sleep-architectural outcomes constitutes the central scientific premise of the present review. An integrative neurochemical framework identifies four distinct sleep-circuit nodes disrupted by hypobaric hypoxia: impaired serotonergic synthesis, an adenosinergic paradox, orexin/hypocretin arousal instability, and locus coeruleus norepinephrine hyperactivation. Each node is mechanistically distinguishable yet interconnected with respiratory loop gain dynamics through shared neurotransmitter pathways, such as serotonin. Additionally, hypoxia-inducible factor-1α (HIF-1α) is examined as a molecular bridge linking hypoxic signalling to circadian clock suppression and dysrhythmia of neurotransmitter synthesis. Current pharmacological agents are reappraised within this dual-target framework, and emerging therapeutic candidates, including GABA-A α₁-selective agents (Z-drugs), α₂-adrenoceptor agonists, orexin receptor antagonists, and adenosine A1-selective antagonists, are critically evaluated. A paradigm shift is proposed: effective management of high-altitude sleep disruption requires simultaneous targeting of both ventilatory control and sleep-circuit neurochemistry.

PMID:
42852772
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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