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ARTICLE, Behavioral/Systems

Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness

Thomas E. Scammell, Ivy V. Estabrooke, Marie T. McCarthy, Richard M. Chemelli, Masashi Yanagisawa, Matthew S. Miller and Clifford B. Saper
Journal of Neuroscience 15 November 2000, 20 (22) 8620-8628; DOI: https://doi.org/10.1523/JNEUROSCI.20-22-08620.2000
Thomas E. Scammell
1Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts,
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Ivy V. Estabrooke
1Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts,
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Marie T. McCarthy
1Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts,
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Richard M. Chemelli
2Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas,
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Masashi Yanagisawa
2Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas,
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Matthew S. Miller
3Cephalon, Inc., West Chester, Pennsylvania, and
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Clifford B. Saper
1Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts,
4Program in Neuroscience, Harvard Medical School, Boston, Massachusetts
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Abstract

Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.

  • modafinil
  • tuberomammillary nucleus
  • lateral hypothalamic area
  • perifornical area
  • orexin
  • hypocretin
  • striatum
  • amygdala
  • suprachiasmatic nucleus
  • anterior hypothalamic area
  • Fos
  • dopamine
  • stimulant
  • narcolepsy
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The Journal of Neuroscience: 20 (22)
Journal of Neuroscience
Vol. 20, Issue 22
15 Nov 2000
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Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness
Thomas E. Scammell, Ivy V. Estabrooke, Marie T. McCarthy, Richard M. Chemelli, Masashi Yanagisawa, Matthew S. Miller, Clifford B. Saper
Journal of Neuroscience 15 November 2000, 20 (22) 8620-8628; DOI: 10.1523/JNEUROSCI.20-22-08620.2000

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Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness
Thomas E. Scammell, Ivy V. Estabrooke, Marie T. McCarthy, Richard M. Chemelli, Masashi Yanagisawa, Matthew S. Miller, Clifford B. Saper
Journal of Neuroscience 15 November 2000, 20 (22) 8620-8628; DOI: 10.1523/JNEUROSCI.20-22-08620.2000
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Keywords

  • modafinil
  • tuberomammillary nucleus
  • lateral hypothalamic area
  • perifornical area
  • orexin
  • hypocretin
  • striatum
  • amygdala
  • suprachiasmatic nucleus
  • anterior hypothalamic area
  • Fos
  • dopamine
  • stimulant
  • narcolepsy

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