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.

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    • "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. "
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    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
    • "Therefore, modafi nil is still an agent in search of a mechanism. Several in vivo and in vitro studies suggest that modafi nil demonstrates an increase in glutamatergic, noradrenergic and dopaminergic transmission in specifi c parts of the brain, and also activates histaminergic tuberomammillary nucleus via inhibition of GABA release (Murillo- Rodriguez et al, 2007, Scammell et al, 2000), which are all known to be involved in pathophysiology of epilepsy. However, its use in epileptic patients is limited due to safety suspicions. "
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    ABSTRACT: Modafinil, is a wake-promoting drug approved by Food and Drugs Administration (FDA) for narcolepsy and sleep-apnoe syndrome. Although the mechanism underlying its arousal action remains elusive, it is known to increase glutamatergic, histaminergic, noradrenergic and dopaminergic transmission and decrease GABA release in different regions of the brain, which are all known to be involved in pathophysiology of epilepsy. In the present study, the effects of modafinil on pentylenetetrazol (PTZ) induced convulsive epilepsy were investigated in rats. Five experimental groups were formed for this purpose and each group was administered five different doses of modafinil (1, 2, 4, 45, 180 mg/kg, i.p) for seven days. All groups were administered PTZ (80 mg/kg, i.p) 2 hours after the final dose and the epileptic seizure activity was evaluated. According to the results; we detected that modafinil delayed the onset of the first myoclonic jerk and decreased the total major seizure period between 2-180 mg/kg doses and did not affect the major seizure onset period at any of the doses administrated. These results imply that modafinil exerts a dose dependent antiepileptic effect on PTZ induced convulsive epilepsy in rats (Tab. 1, Fig. 3, Ref, 42).
    Bratislavske lekarske listy 04/2015; 116(3):162-6. DOI:10.4149/BLL_2015_033 · 0.44 Impact Factor
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    • "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). "

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