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Modafinil and gamma-hydroxybutyrate have sleep state-specific pharmacological actions on hypocretin-1 physiology in a primate model of human sleep


Zeitzer, J M; Buckmaster, C L; Landolt, H P; Lyons, D M; Mignot, E (2009). Modafinil and gamma-hydroxybutyrate have sleep state-specific pharmacological actions on hypocretin-1 physiology in a primate model of human sleep. Behavioural Pharmacology, 20(7):643-652.

Abstract

Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing gamma-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

Abstract

Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing gamma-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:11 September 2009
Deposited On:20 Oct 2009 10:51
Last Modified:05 Apr 2016 13:30
Publisher:Lippincott Wiliams & Wilkins
ISSN:0955-8810
Publisher DOI:https://doi.org/10.1097/FBP.0b013e328331b9db
PubMed ID:19752724

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