Hypothalamic arousal regions are activated during modafinil-induced wakefulness

T. E. Scammell, I. V. Estabrooke, M. T. McCarthy, R. M. Chemelli, Masashi Yanagisawa, M. S. Miller, C. B. Saper

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)8620-8628
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number22
StatePublished - Nov 15 2000

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Wakefulness
Arousal
Lateral Hypothalamic Area
Neurons
Wakefulness-Promoting Agents
Anterior Hypothalamic Nucleus
modafinil
Narcolepsy
Suprachiasmatic Nucleus
Darkness
Gyrus Cinguli
Photoperiod
Sleep
Immunohistochemistry
Pharmacology
Light

Keywords

  • Amygdala
  • Anterior hypothalamic area
  • Dopamine
  • Fos
  • Hypocretin
  • Lateral hypothalamic area
  • Modafinil
  • Narcolepsy
  • Orexin
  • Perifornical area
  • Stimulant
  • Striatum
  • Suprachiasmatic nucleus
  • Tuberomammillary nucleus

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Scammell, T. E., Estabrooke, I. V., McCarthy, M. T., Chemelli, R. M., Yanagisawa, M., Miller, M. S., & Saper, C. B. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal of Neuroscience, 20(22), 8620-8628.

Hypothalamic arousal regions are activated during modafinil-induced wakefulness. / Scammell, T. E.; Estabrooke, I. V.; McCarthy, M. T.; Chemelli, R. M.; Yanagisawa, Masashi; Miller, M. S.; Saper, C. B.

In: Journal of Neuroscience, Vol. 20, No. 22, 15.11.2000, p. 8620-8628.

Research output: Contribution to journalArticle

Scammell, TE, Estabrooke, IV, McCarthy, MT, Chemelli, RM, Yanagisawa, M, Miller, MS & Saper, CB 2000, 'Hypothalamic arousal regions are activated during modafinil-induced wakefulness', Journal of Neuroscience, vol. 20, no. 22, pp. 8620-8628.
Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal of Neuroscience. 2000 Nov 15;20(22):8620-8628.
Scammell, T. E. ; Estabrooke, I. V. ; McCarthy, M. T. ; Chemelli, R. M. ; Yanagisawa, Masashi ; Miller, M. S. ; Saper, C. B. / Hypothalamic arousal regions are activated during modafinil-induced wakefulness. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 22. pp. 8620-8628.
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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.",
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AU - Scammell, T. E.

AU - Estabrooke, I. V.

AU - McCarthy, M. T.

AU - Chemelli, R. M.

AU - Yanagisawa, Masashi

AU - Miller, M. S.

AU - Saper, C. B.

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N2 - 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.

AB - 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.

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