How Does Modafinil Work In The Brain

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How Does Modafinil Work In The Brain – Focusing on receptors and neurotransmitters.

Modafinil is a eugeroic that has been accepted by the FDA in 1998 as a treatment for numerous disorders such as shift work sleep disorders, enhanced daytime sleepiness and shift work sleep disorder (Saletu &Saletu-Zyhlarz, 2013, 231). This drug possesses similar traits to amphetamines and improves the previously mentioned conditions by stimulating neural activity. According to its chemical structure and properties, Modafinil may be classified as a CNS stimulant however; the drug interestingly is not accompanied with side effects that are observed after usage of drugs in the same classification (Saletu &Saletu-Zyhlarz, 2013, 231). Side effects that are common in CNS stimulants but are not observed in Modafinil users include arterial hypertension and tachycardia. The absence of these effects has been widely attributed to the drug’s mechanism of action, though the exact principles of this yet to be established. The paper will focus on the positive effects of the drug and its pharmacokinetics on neural activity.


There have been several theories formulated on the mechanism of neurostimuation by Modafinil. Among these include the histamine effect and the increment of the neurotransmitter dopamine by inhibiting its uptake therefore leaving sufficient amounts for transmission of neurosynaptic impulses. However, theories have suggested that the involvement of dopamine in this action is minimal; hence the different side effects (Saletu &Saletu-Zyhlarz, 2013, 231). The drug is also assumed to increase the availability of other neurotransmitters such as norepinephrine. These mechanisms will be explained in detail in the following section.

Among the numerous theories that have been formulated, one that is most indicative from the author’s research findings is the theory suggesting interaction and activity of Reticular Activating System neurons in the rhombencephalon with Modanifil (Rasetti et al., 2010, 2101-2109). These neurons have been found to be responsible for sustaining arousal levels in humans. The drug has a different impact on the RAS than other neurostimulators such as amphetamine and methylphenitade. Researchers have stated that effects of this drug on the above mentioned structures involve glutamate, hypocretin, ?-aminobutyric acid, norepinephrine, epinephrine, histamine and dopamine (Rasetti et al., 2010, 2101-2109).

neurotransmitters modulation by modafinil


Modafinil has been found to increase the synthesis and release of norepinephrin by altering activity in the locus coeruleus to low tonic and high phasic (Volkow et al., 2009, 1148-1154). The drug possesses an agonistic effect on alpha 1 adrenergic receptors; hence it has a direct stimulatory effect resulting in the inhibition of norepinephrine uptake (Saletu &Saletu-Zyhlarz, 2013, 231). Therefore, this neurotransmitter is increased and has positive impacts on several centers of the brain promoting wakefulness. Some of the effects that occur as a result of increased norepinephrine include increased memory, cerebral plasticity and learning and attention. It also stimulates the Autonomic nervous system, particularly the sympathetic, and increases heart rate and blood pressure leading to enhanced levels of energy (Saletu &Saletu-Zyhlarz, 2013, 231).

Another mechanism that has been suggested involves the elevation in histamine levels. This is due to the effect of Modafinil on receptors of neurons containing peptides which are known as orexins. Specifically these receptors are known as orexin 1 and 2 (Rasetti et al., 2010, 2101-2109). These neurons radiate to different parts of the cerebral cortex, and have been found to also influence centers of involved in sustaining arousal levels and wakefulness. These neurons have also been found to increase the level of neurotransmitters such as noradrenalin and dopamine in the above mentioned areas (Volkow et al., 2009, 1148-1154). The involvement of dopamine in the effects of Modafinil will be explained further in the paper. The above mentioned orexin neurons activated by Modafinil also affect and interact with the posterior hypothalamus, particularly histaminergic tuberomamillary nucleus resulting in an elevated amount of histamine neurotransmitter availability (Rasetti et al., 2010, 2101-2109). The neurons from these nuclei project to numerous areas in the brain regulating numerous neural processes.

As mentioned above, the impacts on the level of dopamine due to Modafinil are even less understood than other neurotransmitters such as norepinephrine and histamine. In fact the drug was first synthesized as a distinct pharmaceutical from other central nervous system stimulants that elevate the level of extra cellular dopamine. However, recent research has discovered that this drug also has an impact on dopamine transporters. Modafinil was found to inhibit these transporters and elevate dopamine levels in the nucleus accumbens and other parts of the brain. Therefore, an elevated amount of dopamine in the brain results in the improvement of several functions such as pleasurable reward, wakefulness, mood and enhanced cognition.

In summation, Modafinl is an eugeroic which has a positive impact on treating narcolepsy and promoting wakefulness. The mechanism of action of this drug has not been fully established, however, a correlation has been found between some neurotransmitters and the use of Modafinil. It has been found to influence receptors on the locus coerulens, nucleua accumbens and tuberomamillary nuclei in the posterior hypothalamus (Volkow et al., 2009, 1148-1154). These centers increase the levels of noreadrenilin, dopamine and histamine respectively. The increase of these neurotransmitters is responsible for the effects produced by Modafinil such as wakefulness (Volkow et al., 2009, 1148-1154).


Rasetti, R., Mattay, V. S., Stankevich, B., Skjei, K., Blasi, G., Sambataro, F., … & Weinberger, D. R. (2010). Modulatory effects of

modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology, 35(10), 2101-2109.

Saletu, M. T., & Saletu-Zyhlarz, G. (2013). Moda?nil effects in narcolepsy.Neuroimaging of Sleep and Sleep Disorders, 231.

Scories et al., 2012. Neurotransmitters modulation by modafinil.

Volkow, N. D., Fowler, J. S., Logan, J., Alexoff, D., Zhu, W., Telang, F., … & Apelskog-Torres, K. (2009). Effects of modafinil on

dopamine and dopamine transporters in the male human brain. JAMA: the journal of the American Medical Association, 301(11), 1148-1154.


  • Sage

    Great article. It makes sense that modafinil acts on both dopamine and serotonin. That must be how the drug improves focus so noticeably.

  • katamandoo

    what does “DAT” stand for in the first image? thanks.