Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness

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.

Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients

“…Modafinil is thought to primarily act on hypocretin (orexin)-containing neurons in the hypothalamus and on the tuberomammillary nucleus, both of which are implicated in the regulation of wakefulness. 16 In contrast, in autopsy studies of polio patients, many other regions in the brainstem and basal ganglia were also affected. 2,3 Also, histologic, imaging and neuroendocrine studies in polio patients showed that the motor cortex, basal ganglia, and reticular activation system bore the brunt of injury.…”

The brain H3-receptor as a novel therapeutic target for vigilance and sleep–wake disorders

“…Thus the absence of sleep rebound associated with modafinil could also be interpreted as absence of catecholamine exhaustion as the waking effect of modafinil does not seem to depend on endogenous catecholamines [35]. Moreover, no signs of direct neuronal depolarization/excitation on target cells have been reported for modafinil, even though diffuse expression of immediate early gene c-fos [41], or enhanced histamine release [42] occurred with high doses of modafinil. These effects can be attributed to a direct consequence of the sustained waking induced by modafinil rather than a direct pharmacological targeted action per se.…”

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

“…The compound does not activate and may inhibit phosphatidylinositol hydrolysis in mouse cortical brain slices yet it does stimulate a prazosin-or terazosinblockable phosphorylation of MAP kinase (MAPK) both in vitro and in vivo but only at fairly high concentrations (10 À4 M) (Stone et al, 2001d). Since it was the only (presumed) a 1 -agonist used in the above study, the possibility that stress may have acted on other neuronal systems necessary for modafinil action such as DA, orexin, or GABA (Ferraro et al, 1997;Scammell et al, 2000) cannot yet be excluded.…”