How Does Modafinil Enhance Wakefulness in the Brain?

Modafinil Online is a wakefulness agent that enhances alertness in a dose-dependent manner. It has also been shown to improve performance on various cognitive tasks in healthy subjects who are sleep-deprived.

One study found that single-dose modafinil 400 mg significantly reduced errors on the Wisconsin Card Sort Test and interference on the Stroop task (compared to placebo) in adults 85 h after sleep deprivation.

Dopamine Receptors

While it is not known for certain, it is thought that Modafinil binds to the dopamine transporter (DAT) in the brain and inhibits the reuptake of dopamine. This causes a rise in dopamine levels and enhances the action of other arousal chemicals.

A recent study using positron emission tomography (PET) found that modafinil increases the amount of dopamine in the striatum, an area of the brain involved in movement, reward, and motivation. The researchers administered the wakefulness drug to healthy human volunteers and then scanned their brains with PET, which uses a radioactive tracer that binds to D2-type receptors in the striatum. They found that the use of modafinil resulted in a greater increase in dopamine activity than did caffeine alone.

It has also been shown that modafinil can enhance performance and alertness in sleep-deprived people. This is due to its ability to stimulate the fronto-parietal regions of the brain which are associated with cognitive functions. Unlike many traditional waking drugs, such as amphetamine and dextroamphetamine, modafinil does not cause the elevation of dopamine in the nucleus accumbens which can lead to addiction and drug abuse.

It is also reported that Modafinil can reduce the symptoms of fatigue and sedation in patients with conditions such as multiple sclerosis, idiopathic Parkinson’s disease, chronic fatigue syndrome, fibromyalgia, narcolepsy, shift work sleep disorder, and post-anesthesia sedation. This is probably due to its effect on dopamine, and the activation of the adrenergic system.

GABA Receptors

GABA (-aminobutyric acid) is a neurotransmitter that mediates inhibitory synaptic transmission in most neurons of the mammalian central nervous system. Agonist activation of the GABA receptors results in hyperpolarization of the cell membrane and inhibition. Modafinil has been shown to increase waking and daytime alertness in narcoleptic patients, as well as to improve objective measures of vigilance.

The improvement in vigilance observed with Modalert Tablet is associated with changes in the power of the a-2 and b-1-3 components of the evoked EEG. The a-2 component is associated with sleepy and inattentive states, while the b-1-3 component is associated with wakefulness and alertness. The remediation of narcolepsy-related sleepiness and improved vigilance with modafinil is also accompanied by improvements in cognitive performance, such as attention and concentration.

Modafinil is an antagonist at the dopamine transporter (DAT). This activity is believed to be responsible for its augmentation of waking and daytime alertness, as evidenced by the fact that the effects of modafinil on the waking state are abolished in DAT-knockout mice.

It has been proposed that modulation of the GABAA receptor may also be involved in the mediation of modafinil’s promoting effects. This is suggested by the observation that modafinil increases the synthesis of GABA in slices of the rat hypothalamus. Furthermore, it has been shown that the pharmacologically selective GABAA receptor antagonists baclofen and clonidine reduce the stimulant effects of modafinil.

Adrenaline Receptors

Modafinil is a wake-promoting drug that has demonstrated efficacy in several studies of patients with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Modafinil has been shown to increase the amount of time a person can stay awake during the day and improve scores on objective measures of alertness, such as the Pauli test. In addition to its wake-promoting effects, modafinil appears to enhance activity in brain areas that serve as a conductor for skills like attention and learning.

The exact mechanism by which modafinil promotes wakefulness is not fully understood. However, it has been shown to potentiate adrenergic neurotransmission by blocking the inhibitory terminal-adrenergic autoreceptors to augment NE release (Lin et al 1992) and by increasing post-synaptic adrenergic receptor activation in the brainstem (Duteil et al 1979). Modafinil is a racemate and its R enantiomer (armodafinil) is superior to the D enantiomer in promoting wakefulness (Dinges et al 2006).

In a double-blind placebo-controlled study of 196 medication-free narcolepsy patients, modafinil significantly improved performance on the Pauli test, and changes in EEG were observed, suggesting that modafinil affects alertness by enhancing activity in brain areas that serve as a conduit for alertness, such as the frontal and anterior cingulate cortices.

Interestingly, an fMRI study of narcolepsy patients treated with modafinil showed that this treatment was associated with increased activation in brain areas associated with learning and attention (Ellis et al 1999). The increase in activity in these regions may be a result of increased blood flow to these areas induced by the drug.

Acetylcholine Receptors

Modafinil does not directly bind to DAT and inhibits DAT uptake in brain cells expressing DAT (Hermant et al, 1991). However, it has been shown to augment the activity of DAT-containing neurons in the monkey prefrontal cortex. This effect is potentiated by pre-treatment with the a2 antagonist yohimbine, suggesting that modulation of the a2 receptor plays an important role in the behavioral effects of modafinil.

In one double-blind placebo-controlled study, a 4-day course of modafinil 200 mg/day significantly reduced errors in a WCST and a version of the Hayling sentence completion task that requires cognitive control. These improvements are associated with the activation of the dorsolateral prefrontal cortex and anterior cingulate cortex.

Moreover, in another double-blind placebo-controlled study of shift-work sleep disorder patients, modafinil increased scores on the work performance and fatigue components of the Profile of Mood States. This increase was associated with a reduction in the time it took to complete the work performance and fatigue components of the test.

Finally, in a small clinical trial of narcolepsy patients, modafinil was found to improve objective measures of wakefulness and to decrease the number of cataplexy events in these patients. Modafinil also induced improvements in self-reported vigor and mood. These results were consistent with a previous larger randomized double-blind placebo-controlled study of modafinil in narcolepsy patients. Read More Blog…