Modafinil Mechanism Of Action (MOA) Explained

Have you ever wondered how Modafinil works in the brain?

And what the mechanism of action for this powerful drug is?

This article will take a closer look at the Mechanism of action for Modafinil.

We will discuss how the drug affects the brain and produces its wakefulness-inducing effects.

So if you're ready, let's dive in!

The Mechanism of Action for Modafinil 

Modafinil's mechanism of action is still somewhat elusive, but it is known to stimulate the brain's histamine (HA), norepinephrine (NE), serotonin (5-HT), dopamine (DA), and orexin systems. This stimulation likely mediates the drug's ability to promote wakefulness and counteract cellular damage [1]Gerrard, Paul, and Robert Malcolm. “Mechanisms of modafinil: A review of current research.” Neuropsychiatric disease and treatment vol. 3,3 (2007): 349-64..

Current research suggests that Modafinil functions as a weak dopamine reuptake inhibitor and indirect activator of the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus (TMN), respectively [2]Scammell, T E et al. “Hypothalamic arousal regions are activated during modafinil-induced wakefulness.” The Journal of neuroscience : the official journal of the Society for Neuroscience vol. … Learn more.

According to one study, Modafinil was shown to have a weaker affinity for the dopamine transporter than other common psychostimulants such as methylphenidate [3](PDF) modafinil as a catecholaminergic agent: Empirical ... - researchgate. (n.d.). Retrieved August 3, 2022, from … Learn more:

The binding to the dopamine transporter increases dopamine release from presynaptic terminals while binding to the norepinephrine reuptake site reduces norepinephrine reuptake into neurons.

Additionally, Modafinil has been shown to bind to the trace amine-associated receptor 1 (TAAR1), which may account for some of its cognitive-enhancing effects [4]Schwartz, M. D., Palmerston, J. B., Lee, D. L., Hoener, M. C., & Kilduff, T. S. (2018). Deletion of trace amine-associated receptor 1 attenuates behavioral responses to caffeine. Frontiers in … Learn more.

Dopaminergic System

Modafinil increases dopamine levels in the synaptic cleft by blocking the dopamine transporter (DAT) and inhibiting its reuptake. This increase in dopamine levels is responsible for the wake-promoting effects of Modafinil [5]Volkow, Nora D et al. “Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.” JAMA vol. 301,11 (2009): 1148-54. doi:10.1001/jama.2009.351.

Modafinil also increases glutamate's extracellular levels, a neurotransmitter that activates the NMDA receptors.

The activation of these receptors results in the enhancement of long-term potentiation (LTP), a process thought to be important for learning and memory.

Histaminergic System

Modafinil binds to the same site on the histamine receptor as do the histamine molecules. This activates the receptor and causes it to open.

This allows more histamine to be released from cells in the brain. The increased histamine levels then cause many of the effects of modafinil, such as wakefulness, increased energy, and improved focus [6]Ishizuka, Tomoko et al. “Action of modafinil through histaminergic and orexinergic neurons.” Vitamins and hormones vol. 89 (2012): 259-78. doi:10.1016/B978-0-12-394623-2.00014-7. This is also referred to as the orexinergic system.

The orexinergic system is responsible for regulating wakefulness and sleep. Modafinil's binding to the orexin receptors increases histamine release, which leads to wakefulness.

Adrenergic System

The adrenergic system is responsible for the body's response to stress. It activates the "fight or flight" response, which increases heart rate and blood pressure, and causes other changes that prepare the body to deal with a stressful situation [7]Wisor, J P, and K S Eriksson. “Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.” Neuroscience vol. 132,4 (2005): 1027-34. doi:10.1016/j.neuroscience.2005.02.003.

Modafinil appears to affect the adrenergic system in two ways:

First, it seems to increase the activity of certain neurotransmitters in the brain that are involved in the fight or flight response.

Second, it seems to block receptors in the brain that normally bind adrenaline, preventing it from having its usual effects. Both of these effects together appear to result in a generalized increase in arousal and alertness.

Modafinil Preclinical Animal Studies

One of the first studies ever done on Modafinil found that it binds weakly to the dopamine transporter and is not selective for any other receptors.

The scientists were skeptical that Modafinil blocks the dopamine transporter and pointed out that it has more potent behavioral effects than some molecules that bind with a much greater affinity to the dopamine reuptake transporter [8]Mignot, E et al. “Modafinil binds to the dopamine uptake carrier site with low affinity.” Sleep vol. 17,5 (1994): 436-7. doi:10.1093/sleep/17.5.436.

Another study looked at the effects of Modafinil and Dexamphetamine on locomotion in rodents and the effects of blocking dopamine receptors. Modafinil showed no significant locomotor effect in reserpine-treated animals, indicating that its effects are not mediated through dopamine receptors.

This study aimed to investigate the effects of Amphetamine and Modafinil on dopamine release in rat synaptosomes. Synaptosomes are small sacs of cells that act as the junctions between nerve cells, and are therefore responsible for transmitting messages between them.

The results of the study showed that while Amphetamine caused a significant increase in spontaneous dopamine release, Modafinil had no effect. This suggests that Amphetamine may be more likely to cause addiction than Modafinil [9]Simon, P et al. “Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice.” European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology … Learn more.

A third study published in the European Journal of Pharmacology looked at the effects of Modafinil on GABA outflow in guinea pigs. The study found that pretreatment with 5,7-dihydroxytryptamine (5,7-DHT) reversed the Modafinil-induced increase in GABA outflow and that Prazosin (an α1 blocker) blocked this effect.

In vitro experiments also showed that Modafinil did not affect [3H]GABA release or uptake. The study concludes by suggesting that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by Modafinil of the GABAergic release in the cerebral cortex [10]Tanganelli, S et al. “Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins.” European journal of pharmacology vol. 273,1-2 (1995): 63-71. … Learn more.

Lastly, one study looked at Modafinil's effect on the neuropeptide orexin (hypocretin) in mice. This study aimed to determine the role of the neuropeptide orexin in sleep/wakefulness states.

Orexin knockout mice were used as a model of human narcolepsy, which is characterized by REM sleep dysregulation. The study found that orexin knockout mice exhibit a phenotype similar to human narcolepsy patients and that Modafinil activates orexin-containing neurons.

These findings suggest that orexin regulates sleep/wakefulness states and that Modafinil may have therapeutic potential for treating narcolepsy [11]Chemelli, R M et al. “Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.” Cell vol. 98,4 (1999): 437-51. doi:10.1016/s0092-8674(00)81973-x.

Modafinil Neurocognitive Studies

One study found that Modafinil increases the cortical pool of glutamate-glutamine, aspartate, inositol, and creatine-phosphocreatine.

It attributes Modafinil's neuroprotective effects to its ability to increase creatine-phosphocreatine and its wake-promoting actions to the resultant increased metabolic activation [12]Piérard, C et al. “Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study.” Brain research vol. 693,1-2 (1995): 251-6. doi:10.1016/0006-8993(95)00711-x.

Another study found that Modafinil prevented a further reduction in GABA release, seen in the cells exposed to glutamate but not Modafinil.

This suggests that Modafinil has a neuroprotective effect against glutamate cytotoxicity. Additionally, the study found that Modafinil did not have an effect on GABA release or uptake in neurons not exposed to glutamate, indicating that Modafinil does not simply stimulate additional GABA release [13]Antonelli, T et al. “Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.” Neuroreport vol. 9,18 (1998): 4209-13. doi:10.1097/00001756-199812210-00038.

Lastly, a study published by Jenner P, Zeng BY, et al. investigated Modafinil's neuroprotective and anti-parkinsonian effects in monkeys treated with MPTP (a prodrug to the neurotoxin MPP).

The first study found that the MPTP-induced parkinsonism symptoms could be improved with Modafinil 11 months after MPTP administration. In the second study, they found that Modafinil administration with MPTP was unable to prevent initial locomotor effects of MPTP but was able to restore locomotor activity within 2 weeks.

They concluded that Modafinil stimulates locomotor effects in already injured animals, and that Modafinil is neuroprotective [14]Jenner, P et al. “Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.” Experimental brain research vol. 133,2 (2000): 178-88. doi:10.1007/s002210000370.

Modafinil's Action on Cytochromes

Cytochromes are a class of enzymes responsible for many drugs' metabolism. Modafinil is a drug that has been shown to increase the activity of some cytochromes, including CYP3A4 and P450 (CYP).

One study showed that Modafinil binds to these enzymes and prevents them from being metabolized, thus increasing its activity. In addition, Modafinil has been shown to induce the expression of certain cytochrome P450 enzymes [15]Robertson, P et al. “In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.” Drug metabolism and disposition: the biological fate of chemicals vol. 28,6 (2000): … Learn more

According to Robertson et al., this induction is thought to be mediated by the drug's ability to increase the transcription of genes that encode these enzymes. As a result, Modafinil can increase the activity of both inhibiting and inducing cytochrome P450 enzymes. This makes the drug an attractive option for the treatment of hepatic disorders.

Unexplored Mechanisms of Modafinil

While the mechanisms of action described above provide some insight into how Modafinil works, there are still many unanswered questions about the drug.

For example, it is unknown how Modafinil crosses the blood-brain barrier or why the drug has different effects in different brain regions. Additionally, the long-term effects of Modafinil use are still not well understood.

Most research into Modafinil’s wake-promoting mechanism has focused on its possible extracellular activities. However, Gerrard et al. propose that more work be done on examining potential intracellular mechanisms of Modafinil and finding a point of convergence of its stimulant and neuroprotective effects.

They hypothesize that Modafinil enhances cellular metabolism and reduces free radicals in neurons, which could promote vigilance.

Additionally, reduced brain oxidation or increased cortical creatine could promote neurotransmitter release by reducing inhibitory KATP-channel activity.

Thus, Modafinil could enhance vigilance through any disruption in the positive feedback loop of increased free radical production and reduced brain oxidation.

Modafinil and KATP-channel Activity

As Gerrard et al. suggest, one potential mechanism of Modafinil’s action is its ability to reduce KATP-channel activity.

KATP (KATP) channels are important in regulating cell metabolism and intracellular signaling. KATP-channel activity is the opening and closing of K+ channels in response to changes in the cell's membrane potential.

This activity is regulated by the ATP-sensitive potassium (KATP) channel. The KATP channel is activated by an increase in the cell's ATP concentration and is inhibited by a decrease in the cell's ATP concentration [16]Szeto, V., Chen, N.-hong, Sun, H.-shuo, & Feng, Z.-ping. (2018, April 19). The role of KATP channels in cerebral ischemic stroke and diabetes. Nature News. Retrieved August 5, 2022, from … Learn more.

This means that when the cell has high ATP concentrations, the KATP channel is open, and potassium ions can flow into the cell. This activity has an inhibitory effect on cell metabolism.

Conversely, when the cell has low ATP concentrations, the KATP channel is closed, and potassium ions cannot flow into the cell. This activity has a stimulatory effect on cell metabolism.

Concerning Modafinil, it is thought that the drug reduces KATP-channel activity, which leads to an increase in cell metabolism. This increase in cell metabolism could explain Modafinil's wake-promoting effect.

Additionally, this mechanism could also explain Modafinil's neuroprotective effect. KATP-channel activity has been linked to cell death after cerebral ischemia [17]Szeto, Vivian et al. “The role of KATP channels in cerebral ischemic stroke and diabetes.” Acta pharmacologica Sinica vol. 39,5 (2018): 683-694. doi:10.1038/aps.2018.10.

Modafinil Mechanism Of Action: Conclusion

While the exact mechanisms of Modafinil are still unknown, research has provided some insight into how the drug works.

Modafinil is thought to work by increasing the activity of both inhibiting and inducing cytochrome P450 enzymes. Additionally, Modafinil is thought to reduce KATP-channel activity, which leads to an increase in cell metabolism.

Modafinil also works on the dopaminergic, histaminergic, and adrenergic systems. This is why Modafinil has both wake-promoting and cognitive-enhancing effects.

Further research is needed to fully understand the mechanisms of Modafinil. However, the current research suggests that Modafinil is a promising drug for treating sleep disorders and cognitive impairment.

References

References
1Gerrard, Paul, and Robert Malcolm. “Mechanisms of modafinil: A review of current research.” Neuropsychiatric disease and treatment vol. 3,3 (2007): 349-64.
2Scammell, T E et al. “Hypothalamic arousal regions are activated during modafinil-induced wakefulness.” The Journal of neuroscience : the official journal of the Society for Neuroscience vol. 20,22 (2000): 8620-8. doi:10.1523/JNEUROSCI.20-22-08620.2000
3(PDF) modafinil as a catecholaminergic agent: Empirical ... - researchgate. (n.d.). Retrieved August 3, 2022, from https://www.researchgate.net/publication/257600321_Modafinil_as_a_Catecholaminergic_Agent_Empirical_Evidence_and_Unanswered_Questions
4Schwartz, M. D., Palmerston, J. B., Lee, D. L., Hoener, M. C., & Kilduff, T. S. (2018). Deletion of trace amine-associated receptor 1 attenuates behavioral responses to caffeine. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.00035 
5Volkow, Nora D et al. “Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.” JAMA vol. 301,11 (2009): 1148-54. doi:10.1001/jama.2009.351
6Ishizuka, Tomoko et al. “Action of modafinil through histaminergic and orexinergic neurons.” Vitamins and hormones vol. 89 (2012): 259-78. doi:10.1016/B978-0-12-394623-2.00014-7
7Wisor, J P, and K S Eriksson. “Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.” Neuroscience vol. 132,4 (2005): 1027-34. doi:10.1016/j.neuroscience.2005.02.003
8Mignot, E et al. “Modafinil binds to the dopamine uptake carrier site with low affinity.” Sleep vol. 17,5 (1994): 436-7. doi:10.1093/sleep/17.5.436
9Simon, P et al. “Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice.” European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology vol. 5,4 (1995): 509-14. doi:10.1016/0924-977x(95)00041-m
10Tanganelli, S et al. “Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins.” European journal of pharmacology vol. 273,1-2 (1995): 63-71. doi:10.1016/0014-2999(94)00675-w
11Chemelli, R M et al. “Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.” Cell vol. 98,4 (1999): 437-51. doi:10.1016/s0092-8674(00)81973-x
12Piérard, C et al. “Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study.” Brain research vol. 693,1-2 (1995): 251-6. doi:10.1016/0006-8993(95)00711-x
13Antonelli, T et al. “Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.” Neuroreport vol. 9,18 (1998): 4209-13. doi:10.1097/00001756-199812210-00038
14Jenner, P et al. “Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.” Experimental brain research vol. 133,2 (2000): 178-88. doi:10.1007/s002210000370
15Robertson, P et al. “In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.” Drug metabolism and disposition: the biological fate of chemicals vol. 28,6 (2000): 664-71.
16Szeto, V., Chen, N.-hong, Sun, H.-shuo, & Feng, Z.-ping. (2018, April 19). The role of KATP channels in cerebral ischemic stroke and diabetes. Nature News. Retrieved August 5, 2022, from https://www.nature.com/articles/aps201810
17Szeto, Vivian et al. “The role of KATP channels in cerebral ischemic stroke and diabetes.” Acta pharmacologica Sinica vol. 39,5 (2018): 683-694. doi:10.1038/aps.2018.10
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