After years of preclinical research, Modafinil was added to the narcolepsy armamentarium in 1998. Since then, a large body of clinical and experimental evidence has been generated to support its use in various sleep disorders and other conditions.
Modafinil Tablets Australia has been shown to increase the brain’s creatine-phosphocreatine pool. It may act via this mechanism to reduce free radical activity throughout the brain, including in specific regions such as the basal forebrain.
Modafinil Increases Delta Activity
Dopamine neurons in the VTA and Sync are important for Modafinil wake-promoting actions, but it is not clear which of their dopamine signaling pathways is responsible. Using a dopamine indicator, dLight1.1, we found that Modafinil increases wakefulness by increasing EEG delta activity in the locus cerulean (Figure S3A) and dorsal striatum (Figure S3B). Furthermore, the blockade of D1 or D2 receptors abolished these effects.
Similarly, we have shown that narcoleptic patients have decreased power in the delta band of the EEG. Modafinil increases this power and also reduces the decrease in power of the gamma band seen with d-amphetamine.
The reason for this is not known, but it may be related to the anti-oxidative effects of Modafinil. It is believed that oxidative species produced by the normal brain during wakefulness increase extracellular adenosine levels and induce sleepiness. Modafinil antioxidant properties lower oxidative species levels and thus reduce adenosine accumulation in the basal forebrain.
Another potential mechanism is that Modafinil increases serotonin release. However, a [11C]raclopride study of Modafinil in rats showed that it did not increase cortical serotonin transmission. This was consistent with other studies demonstrating that Modafinil does not cause direct increases in serotonin reuptake. It does, however, bolster the effects of classic serotonin uptake inhibitors given at sub-threshold doses.
Modafinil Increases Theta Activity
Although many wake-promoting compounds affect EEG delta and theta power, their effects on gamma activity are often overlooked. To address this issue, we studied the effects of d-amphetamine, Modafinil, and YKP10A on wakefulness (2 h) and EEG gamma activity (35-60 Hz) in three inbred mice genotypes.
The results showed that the wake duration induced by YKP10A and Modafinil depended on genotype, but only Modafinil increased theta oscillation frequency and power, as well as beta-2 activity. Interestingly, neither 18b-glycyrrhetinic nor carbenoxolone preincubation prevented the effects of Modafinil on VSDI and intracellular recordings.
The increase in gamma activity induced by Modalert 200 mg was associated with increased input conductance in pyramidal neurons. However, Modafinil did not alter EPSC amplitudes during paired-pulse stimulation in control or Modafinil-treated cells. This indicates that the increase in gamma activity is not due to an increase in the amplitude of synaptic transmission but rather a reduction in input resistance.
Modafinil has been shown to enhance brain metabolism and decrease oxidative damage by increasing the pool of glutamate-glutamine, aspartate, inositol, and creatine-phosphocreatine in cortical neurons by inhibiting KATP channel activation. Although these effects may be indirectly or even entirely extracellularly mediated, they could contribute to Modafinil stimulant effects by increasing neurotransmitter release.
In addition, a recent paper by Madras and colleagues suggests that Modafinil increases DA, 5-HT, and NE levels in the cortex through an unknown mechanism that does not involve increasing DAT and/or NET activation (Citation Madras et al 2006). Therefore, a combination of extracellular and intracellular mechanisms likely underlie the effects of Modafinil on awake EEG activity.
Modafinil Increases Alpha Activity
Modafinil is a stimulant that does not increase blood pressure as much as amphetamines do. It is also unlikely to cause addiction or abuse.
Modafinil increases levels of the adenosine triphosphate (ATP) molecule in the brain and this is associated with increased activity. However, the mechanism of action is unclear. It may act through a combination of mechanisms.
One possibility is that it directly inhibits dopamine reuptake in the VLPO and promotes wakefulness by inhibiting the orexin neurons. Another possible mechanism is that it indirectly inhibits noradrenaline reuptake in the VLPO by acting as an alpha 1B-adrenergic agonist and increasing orexin activation.
Alternatively, it may act as an indirect NMDA receptor antagonist or via an unknown upstream site. Modafinil increases the synthesis of ATP and it has been shown that this is associated with an increase in awake EEG activity.
In a study of frontal, parietal, and occipital electrodes, Modafinil increased power in the theta-alpha and beta-beta ranges. However, these effects were more dispersed in time and frequency than the placebo-treated group.
Modafinil has been shown to increase HA, NE, 5-HT, and DA in various brain regions including the medial preoptic area of the hypothalamus, the hippocampus, and the nucleus accumbens and pallidum. In addition to these increases, it reduces GABA in the same brain regions. GABA inhibition by Modafinil is mediated by the serotonin receptor.
Modafinil Increases Beta Activity
EEG slow wave activity (SWA, 0.75-4.5 Hz) is a reliable marker of homeostatic sleep pressure in NREM sleep and declines during waking. Using an empirically thresholder spectrogram technique, we measured a robust increase in SWA with Modafinil and placebo for high-control vs.
low-control trials of the psychomotor vigilance task in both Val/Val and Met/Met COMT genotypes during the cue-probe delay period of the vigilance test. However, this increase in SWA did not appear to relate to task performance.
In contrast, the adrenergic neurotransmitter norepinephrine (NE) is associated with task performance and increases during waking. NE increases the amount of glutamate released by medial prefrontal cortex pyramidal cells, which causes cellular synapse depolarization and a decrease in the amplitude of slow waves (e.g., SWA).
Modafinil increases NE activity and thus glutamate release in medial prefrontal cortex pyramidal cells (Ferraro et al, 1999), yet the adrenergic receptor antagonists prazosin and yohimbine fail to suppress the wake-promoting effects of Modafinil on these neurons. This suggests that modulation of adrenergic and dopamine signaling in the frontal cortex is responsible for the wake-promoting effects of Modafinil.
Using electroencephalography in live animals, Sebat and colleagues (1999) found that Modafinil bolsters the EEG synchronization induced by the dopamine D2 antagonist raclopride. Modafinil also attenuates the evolution of subjective sleepiness and waking EEG theta power in response to prolonged sleep deprivation independent of the COMT genotype.
