Research ArticleSleep

Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors

Science Translational Medicine  21 Nov 2012:
Vol. 4, Issue 161, pp. 161ra151
DOI: 10.1126/scitranslmed.3004685

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Awake and Refreshed

A spindle prick on the finger, and Princess Aurora couldn’t keep her eyes open; one hundred years later, Sleeping Beauty was awakened with a kiss. But persistent daytime sleepiness—hypersomnolence—is no fairy tale, and neither the cause nor a cure is apparent. Now, Rye et al. begin to illuminate, in patients with primary hypersomnias, the neurobiology that underlies sleepiness of unknown etiology.

A disabling condition, primary hypersomnia is characterized by lethargy, trance-like states, and “sleep drunkenness” even after prolonged, deep, nonrestorative sleep. The authors showed that cerebrospinal fluid (CSF) from these hypersomnolent subjects contains a small (500 to 3000 daltons) trypsin-sensitive substance that stimulates the in vitro function of selected γ-aminobutyric acid (GABA) receptors only in the presence of GABA—an inhibitory neurotransmitter that stimulates GABA receptors, quells consciousness, and induces sleep.

GABA receptors are known to bind a class of psychoactive sedating drugs called benzodiazepines (BZDs). Hypersomnolent CSF samples mimicked the effects of BZD on GABA receptors but did not compete with BZD binding in human brain tissue, suggesting that the newly identified substance functions by a distinct mechanism. Furthermore, the BZD receptor antagonist flumazenil reversed hypersomnolent-CSF activation of GABA signaling, even though the drug is known to be a competitive antagonist of BZD and blocks BZD action by binding to the classical BZD-binding domain of GABA receptors. Most importantly, flumazenil restored vigilance in some hypersomnolent subjects. Together, these mechanistic studies pinpoint a potential new neuropharmacological pathway for a 25-year-old drug.

The current study suggests that one of the “spindle pricks” that puts hypersomnolent subjects to sleep is a substance in CSF that augments inhibitory GABA signaling. A deeper understanding of the neurobiology of primary hypersomnia should help scientists discover new “kisses” that restore wakefulness—in fewer than 100 years.