Cortico-Amygdala-Striatal Activation by Modafinil/Flecainide Combination (original) (raw)
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British Journal of Clinical Pharmacology, 2019
AIMS: THN102 is a novel combination of modafinil and low-dose flecainide, targeting glial connexin activity to modulate modafinil effects. We investigated THN102 efficacy compared to modafinil and to placebo on vigilance and cognitive function during 40-h total sleep deprivation (TSD). METHODS: 20 healthy men participated in a double-blind, randomized, incomplete-block 3period cross-over trial with 5 treatments (n=12 per group): placebo (PBO), modafinil 100 mg (MOD100), THN102 100/1, 100/3, 100/9 (modafinil 100mg and flecainide 1, 3 or 9 mg). Each period included a baseline day and a TSD day with treatments administered three times (01:00, 09:00 and 19:00). Reaction time in Psychomotor Vigilance Test (PVT), subjective somnolence and vital signs were assessed before and during treatment. Working memory (2-Back) and executive processes (Go/noGo for vigilance and inhibition, Wisconsin Card Sorting Task (WCST) for mental flexibility and Tower of London test for planning) were evaluated at 16:30. RESULTS: At 5-h post dose-1 (after 23-h TSD, primary endpoint), THN102 100/1 resulted in statistically higher PVT speed vs. MOD100 (3.97±0.09 vs. 3.74±0.14, p<0.05). No increase in effect was observed with higher flecainide doses in combinations. Most THN102 doses vs. MOD100 also improved the number of correct responses in 2-Back and Go errors in Go/noGo (p<0.05 for all doses), and perseverative responses in WCST (for 100/1 and 100/9). No impact on cardiac conduction was noted with THN102, and safety was similar to MOD100. CONCLUSIONS: THN102 seems more efficient than modafinil on vigilance, working memory and executive functions, opening new perspectives in management of hypersomnolence disorders.
Sleep, 2010
The main energy reserve of the brain is glycogen, which is almost exclusively localized in astrocytes. We previously reported that cerebral expression of certain genes related to glycogen metabolism changed following instrumental sleep deprivation in mice. Here, we extended our investigations to another set of genes related to glycogen and glucose metabolism. We also compared the effect of instrumentally and pharmacologically induced prolonged wakefulness, followed (or not) by 3 hours of sleep recovery, on the expression of genes related to brain energy metabolism. Sleep deprivation for 6-7 hours. Animal sleep research laboratory. Adults OF1 mice. Wakefulness was maintained by "gentle sleep deprivation" method (GSD) or by administration of the wakefulness-promoting drug modafinil (MOD) (200 mg/kg i.p.). Levels of mRNAs encoding proteins related to energy metabolism were measured by quantitative real-time PCR in the cerebral cortex. The mRNAs encoding protein targeting to g...
Modulation of Fronto-Cortical Activity by Modafinil: A Functional Imaging and Fos Study in the Rat
Neuropsychopharmacology, 2011
Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug.
Hypothalamic Arousal Regions Are Activated during Modafinil- Induced Wakefulness
2000
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 num-ber 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.
The central nucleus of the amygdala and the wake-promoting effects of modafinil
Brain Research, 2002
Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905-911; Neurosci. Lett. 241 (1998) 95-98]. The present experiments were designed to test the hypothesis that the ACe is, at least in part, involved in the wake-producing actions of modafinil. In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modafinil into the ACe did not affect sleep architecture. Thus, ACe does not play a simple role in modafinil's wake-promoting action. We suggest that more complex testing will be required to elucidate its role.
Effect of modafinil on cerebral blood flow in narcolepsy patients
Sleep, 2008
To investigate the effects of modafinil on regional cerebral blood flow (rCBF) in narcolepsy, we performed 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo medication. Brain SPECT was performed twice during the awake state before and after modafinil or placebo administration for 4 weeks in 43 drug-naive narcoleptics with cataplexy (M/F = 23/20, 29.5 +/- 5.8 years). For SPM analysis, all SPECT images were spatially normalized to the standard SPECT template and then smoothed using a 12-mm full width at half-maximum Gaussian kernel. The paired t-test was used to compare pre- and post-modafinil or placebo SPECT images. The mean modafinil dose used was 207.8 +/- 62.3 mg/day. Modafinil significantly reduced Epworth Sleepiness Scale scores from 20.3 +/- 2.1 to 5.2 +/- 3.1 (P < 0.01), while placebo did not. Compared to the off-modafinil condition, the on-modafinil condition showed significantly increased rCBF in the righ...
Neuroscience Letters
We investigated whether administration of MOD in rats during the lights-on period into wake-promoting areas, such as anterior hypothalamus (AH) or into the pedunculopontine tegmental nucleus (PPTg) would enhance waking. Results showed that microinjections of 1 L of MOD (10, 20, or 30 g) into both brain areas increased the total time of alertness and decreased sleep. Additionally, MOD-treated rats showed an enhancement in alpha power spectra but delta power spectra was diminished. Finally, c-Fos expression was found increased into either AH or the PPTg. Collectively, these results suggest that MOD induces waking via the activity of two wake-related brain areas such as AH and the PPTg.
Journal of Sleep Research, 2008
To investigate the effects of a wake-promoting drug, modafinil on regional cerebral blood flow (rCBF) in healthy volunteers, we performed 99m Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo administration. Twenty-one healthy subjects received single doses of 400 mg modafinil or placebo in a double blind randomized crossover study design. Administrations of modafinil or placebo in a subject were separated by a 2-week washout. Brain SPECT was performed twice before and 3 h after modafinil or placebo administration. For statistical parametric mapping analysis, all SPECT images were spatially normalized to the standard SPECT template and then smoothed using a 12mm full width at half-maximum Gaussian kernel. The paired t-test was used to compare pre-versus post-modafinil and pre-versus post-placebo SPECT images. Differences in rCBF between post-modafinil and post-placebo conditions were also tested. Modafinil decreased Epworth and Stanford sleepiness scales whereas placebo did not. The post-modafinil condition was associated with increased rCBF in bilateral thalami and dorsal pons, whereas the post-placebo condition showed increased rCBF in a smaller area of the dorsal pons when compared with the drug naı¨ve baseline condition. Compared with the post-placebo condition, the post-modafinil condition showed higher rCBF in bilateral frontopolar, orbitofrontal, superior frontal, middle frontal gyri, short insular gyri, left cingulate gyrus, left middle ⁄ inferior temporal gyri, left parahippocampal gyrus, and left pons. In healthy volunteers, modafinil increased wakefulness and rCBF in the arousal-related systems and in brain areas related to emotion and executive function.
Proceedings of the National Academy of Sciences, 1996
Much experimental and clinical data suggest that the pharmacological profile of modafinil, a newly discovered waking substance, differs from those of amphetamine and methylphenidate, two classical psychostimulants. The brain targets on which modafinil acts to induce wakefulness, however, remain unknown. A double-blind study using the protooncogene c- fos as experimental marker in the cat was, therefore, carried out to identify the potential target neurons of modafinil and compare them with those for amphetamine and methylphenidate. Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or modafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, respectively) and brain sections examined for Fos by immunocytochemistry. Administration of either amphetamine or methylphenidate evoked Fos-like immunoreactivity in a large number of neurons in the striatum and whole cortex, especially in the caudate nucleus and mediofrontal cortex, which are kn...