Modafinil 200 Australia is a new drug used to treat narcolepsy. It was approved for this use in 1998, but the mechanism by which it promotes wakefulness remains a mystery. However, these effects are not the sole cause of modafinil’s wake-promoting actions.
Dopamine
The monoaminergic system has received a lot of attention for its role in the sleep wake cycle. Neurons releasing monoamines, such as dopamine and norepinephrine, are active during wakefulness but silent in REM sleep. Recent studies have shown that the wake-promoting drug modafinil increases histamine and serotonin in the lateral hypothalamus, and has also been reported to increase dopamine levels in SNc and VTA neurons (Gonzalez et al, 1999).
The mechanism of action of modafinil is still unclear, although it appears to enhance neurotransmitter release through increased neuroelectrosecretory coupling. It has been suggested that the drug may improve mitochondrial function and free-radical scavenging, and it is also known to inhibit the activity of cytochrome P450 enzymes involved in oxidative stress and cellular damage.
Modafinil appears to enhance cortical glutamate through inhibition of a GABAergic inhibitory circuit. Della Marca et al (2004) recorded the electro-physiological responses of VLPO neurons in vivo and found that modafinil enhanced subcortical oscillations by inhibiting the noradrenergic inhibition of these cells. They also found that this was due to a decrease in ascending cholinergic tone.
However, they did not find that modafinil significantly increases cortical glutamate. Furthermore, they did not observe any increase in dLight1.1 fluorescence after the administration of a low-dose of modafinil in SNc-dopamine neurons that were lesioned. They did, on the other hand, observe a significant increase in the dLight1.1 fluorescence after a high dose of modafinil.
Orexin
Although modafinil (Modvigil 200 mg) is known as a wakefulness-promoting drug, it also has neuroprotective effects in preclinical studies. One possible mechanism involves reduction of free radicals in the brain and subsequent decreases in adenosine levels.
Adenosine is a sleep-inducing metabolite that increases with prolonged wakefulness and is a powerful inhibitor of the activation of the monoaminergic arousal systems. Modafinil may reduce the production of adenosine by increasing activity in cholinergic neurons and decreasing suppression of the motor excitatory system of the brainstem.
Another potential mechanism is the direct action of modafinil on neurotransmitter release in the locus coeruleus. This effect has been demonstrated by a variety of experiments, including electrophysiological and behavioral studies. Modafinil can cause an increase in the release of norepinephrine and dopamine, as well as cAMP. It can also cause the inhibition of NMDA receptors and the elevation of GABA-A receptors.
Recent studies have shown that the NMDA receptor antagonist yohimbine potentiates the wakefulness-promoting effects of modafinil. These effects have been attributed to the ability of yohimbine to block pre-synaptic a2 autoreceptors, thereby enhancing NE release and augmenting post-synaptic a2 receptor activation (Duteil et al, 1979).
This biphasic response indicates that postsynaptic a2 receptors are involved in the wakefulness-promoting effects of modafinil. The implication is that the modulation of a2 receptors could help to develop more selective pharmacological strategies for disorders in which disordered arousal, such as narcolepsy, is a prominent feature.
Adenosine
Adenosine is one of the body’s most powerful molecules. It is produced when glucose, which comes from the foods we eat, breaks down during digestion. This produces Adenosine Tri-Phosphate (ATP), which is used for energy transfer between cells.
When ATP is “used up”, it decomposes into adenosine, which has the ability to interact with specific cell receptors and inhibit neural activity. When the brain levels of adenosine are high, it can cause drowsiness. This is why it is important to monitor the blood concentrations of adenosine during surgery or other procedures that require prolonged wakefulness.
Recent studies have shown that adenosine has a critical role in the circadian rhythms that govern sleep-wake cycles. Specifically, adenosine inhibits the release of the arousal hormone cortisol. This may lead to a decrease in the number of neurons firing in the locus coeruleus, which normally sends signals that promote wakefulness. Moreover, adenosine also acts to suppress the production of glucocorticoids.
In a series of experiments, researchers investigated the effect of adenosine on sleep-wake behaviors in a PZVgat-hM3Dq mouse model with histologically confirmed VLPO lesions. Their results showed that histologically confirmed VLPO lesions do not block the wake-promoting action of armodafinil, nor does reactivation of these neurons by CNO prevent the effect. However, they did find that reactivation of these neurons prevented the increase in SWS delta power observed with both armodafinil and CNO.
Serotonin
Serotonin is a naturally occurring chemical that acts as a neurotransmitter to carry signals between brain nerve cells (neurons). Most of the body’s serotonin is produced in the lining of the gastrointestinal tract. The remainder is produced in the brain, where it functions to regulate a variety of physiological processes, including sleep.
The link between serotonin and sleep is complex and controversial, but it is well known that sleep disorders such as narcolepsy, shift work disorder and obstructive sleep apnea are associated with low levels of this hormone.
Serum serotonin concentrations increase during wakefulness, and a decrease in these concentrations is associated with sleepiness. Interestingly, modafinil increases circulating serotonin. Whether this is due to its antidepressant properties or the fact that it prevents the degradation of the neurotransmitter by CYP2C enzymes remains unknown.
The arousal and activity-promoting effects of modafinil are primarily a function of changes in catecholamine systems, mainly adrenergic a and b receptors, and noradrenergic DAT occupancy. The reduction in oxidative stress and adenosine levels mediated by modafinil may play a role in these effects, but the precise mechanism of action is unclear. It is possible that this occurs through modulation of adenosine in the basal forebrain, where adenosine exerts its sleep-promoting effects.
Modafinil appears to act in many of the same brain regions as caffeine and amphetamine, but its actions are characterized by more potent wake-promoting effects and less humor-promoting effects. It also does not increase cortical glutamate in the locus coeruleus, which is a major site for pupillary dilation and arousal. Read More Blog…
