Hypothalamic Arousal Regions Are Activated during Modafinil- Induced Wakefulness

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2000; 20(22):8620-8.
Source: PubMed


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.

10 Reads
  • Source
    • "The c-Fos antibody from Santa Cruz Biotechnology (Santa Cruz, CA) was raised against amino acids 3216 near the N-terminus of c-Fos of human origin: FSGFNADYEASSSR and affinity purified. Both c-Fos antibodies stained only neuronal nuclei in the same patterns as previously reported at this time of day for rats that were untreated (Scammell et al., 2000) or exposed to CO 2 (Berquin et al., 2000). The staining patterns with the CTb antibody depended solely on the site of CTb injection; this antibody stains nothing in animals not injected with CTb. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In patients with obstructive sleep apnea, airway obstruction during sleep produces hypercapnia which in turn activates respiratory muscles that pump air into the lungs (e.g. the diaphragm) and that dilate and stabilize the upper airway (e.g., the genioglossus). We hypothesized that these responses are facilitated by glutamatergic neurons in the parabrachial complex (PB) that respond to hypercapnia and project to premotor and motor neurons that innervate the diaphragm and genioglossus muscles. To test this hypothesis we combined c-Fos immunohistochemistry with in situ hybridization for vGluT2 or GAD67 or with retrograde tracing from the ventrolateral medullary region that contains phrenic premotor neurons, the phrenic motor nucleus in the C3-C5 spinal ventral horn, or the hypoglossal motor nucleus. We found that hypercapnia (10% CO2 for 2 hours) activated c-Fos expression in neurons in the external lateral, lateral crescent (PBcr), and Kölliker-Fuse (KF) PB subnuclei and that most of these neurons were glutamatergic and virtually none GABAergic. Numerous CO2 -responsive neurons in the KF and PBcr were labeled after retrograde tracer injection into the ventrolateral medulla or hypoglossal motor nuclei, and in the KF after injections into the spinal cord, making them candidates for mediating respiratory-facilitatory and upper airway stabilizing effects of hypercapnia. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., A Wiley Company.
    The Journal of Comparative Neurology 04/2015; 523(6). DOI:10.1002/cne.23720 · 3.23 Impact Factor
  • Source
    • "systems projecting to cortical areas, i.e. cholinergic and dopaminergic neurons (Ligneau et al., 2007a,b). Both tiprolisant and modafinil enhanced wakefulness during the lights-off (active) period in orexin −/− mice, as is observed in WT rodents (Scammell et al., 2000; Parmentier et al., 2007; Ligneau et al., 2007b) and cats (Lin et al., 1992; Ligneau et al., 1998, 2007a). "
  • Source
    • "Sections were then washed again and incubated in a solution of 0.06% 3,3-diaminobenzidine tetrahydrochloride (DAB; Sigma-Aldrich, St Louis, MI, USA), 0.02% H2O2 and 0.05% cobalt chloride and 0.01% nickel ammonium sulfate. The c-Fos antibody (1:50,000, AB5, ~55kD; EMD Millipore, Billerica, MA, USA) used was a rabbit polyclonal antibody raised against residues 4–17 from human c-Fos, and it stained characteristic patterns of cells in the hypothalamus and cerebral cortex in both waking and sleeping intact rats.15 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons.
    Nature and Science of Sleep 05/2014; 6:57-63. DOI:10.2147/NSS.S53132
Show more

Preview (2 Sources)

10 Reads
Available from