Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Oct;20(7):643-52.
doi: 10.1097/FBP.0b013e328331b9db.

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

Jamie M Zeitzer  1 , Christine L Buckmaster, Hans-Peter Landolt, David M Lyons, Emmanuel Mignot
Affiliations

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

Jamie M Zeitzer et al. Behav Pharmacol. 2009 Oct.

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 γ-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.

PubMed Disclaimer

Conflict of interest statement

Disclosures/Conflicts of Interest: A portion of this study was funded by Jazz Pharmaceuticals (JMZ).

Figures

Figure 1
Figure 1
Average movement from 05:00 until 13:00 in animals exposed to placebo (black), modafinil (light grey), or GHB (dark grey). Data were averaged over an hour within and then between monkeys and are presented as mean ± SEM. The time of darkness is illustrated by a dark bar above the x-axis. The time of drug/placebo administration is indicated by arrows. Integrated actigraphy data (07:00–13:00) is presented in the inset. Significance difference (p<0.05) from control is indicated by an asterisk. Arb = arbitrary units.
Figure 2
Figure 2
Average movement from 17:00 until 01:00 in animals exposed to placebo (black), modafinil (light grey), or GHB (dark grey). Legend as for Figure 1 except the inset shows actigraphy data integrated from 20:00 to 01:00. The time of drug/placebo administration is indicated by arrows (G for GHB, M for modafinil, C for control).
Figure 3
Figure 3
The amount of wakefulness present between 07:00 and 13:00 after administration of the same injected dose of GHB (●) or a placebo injection (○) follows a logistic function [y=A2+(A1−A2)·(1+(x/x0)p)−1].
Figure 4
Figure 4
CSF hypocretin-1 concentration change scores from placebo treatment at 13:00 (left panel) and 01:00 (right panel) after administration of GHB or modafinil. Hypocretin-1 is significantly lower after daytime administration of GHB, when there is an increase in sleep, and is significantly elevated after nighttime modafinil administration, when there is an increase in wakefulness. Hypocretin-1 is increased at 13:00 after modafinil treatment, but this change did not reach statistical significance (p=0.18). Data are plotted as average ± SD percent change in hypocretin-1 concentrations in the drug conditions, as compared to placebo. Percentage data were log transformed before averaging and re-transformed following averaging.
Figure 5
Figure 5
Plasma cortisol concentration change scores from placebo treatment at 13:00 (left panel) and 01:00 (right panel) after administration of GHB or modafinil. Cortisol was significantly elevated after daytime administration of modafinil, but the increase in cortisol after nighttime administration did not reach statistical significance (p=0.25). There was no significant effect of GHB on cortisol. Data are plotted as average ± SD percent change in cortisol concentrations in the drug conditions, as compared to placebo. Percentage data were log transformed before averaging and re-transformed following averaging.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007;450:420–424. - PMC - PubMed
    1. Beardsley PM, Balster RL, Harris LS. Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB) Psychopharmacol. 1996;127:315–322. - PubMed
    1. Béracochéa D, Liscia P, Tronche C, Chauveau F, Jouanin J-C, Piérard C. Stress modulation of the memory retrograde-enhancing effects of the awakening drug modafinil in mice. Psychopharmacol. 2008;196:1–13. - PubMed
    1. Berridge CW, España RA. Hypocretins: waking, arousal, or action? Neuron. 2005;46:696–698. - PubMed
    1. Brun J, Chamba G, Khalfallah Y, Girard P, Boissy I, Bastuji H, Sassolas G, Claustrat B. Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation. J Sleep Res. 1998;7:105–114. - PubMed

Publication types

MeSH terms