Modafinil: What is it?
The FDA approved modafinil, also marketed as Provigil in the US, in 1998 to treat daytime drowsiness brought on by narcolepsy, obstructive sleep apnea, and shift work sleep disorder.(Source: ) Off-label, it is frequently used as a “smart drug” to increase alertness and fight sleepiness.
In order to increase arousal, modafinil is frequently utilized by emergency services and transportation workers. Modafinil has also been utilized by the US Air Force, ISS astronauts, and other military personnel to control fatigue during extended deployments.] Because modafinil was purportedly utilized by professional athletes as a performance enhancer, the World Anti-Doping Agency banned it in 2004.
The Action Mechanism of Modafinil
A lot of psychostimulants, like methylphenidate and amphetamine, block the dopamine active transporter, which raises the amount of dopamine outside of cells. The way modafinil works, though, seems to be different because it functions as a dopamine reuptake inhibitor only weakly and selectively.
200 and 300 mg of modafinil cause 51.4% and 56.9% dopamine active transporter (DAT) occupancy in the striatum in human PET scans. This region includes the nucleus accumbens, which is an important part of the mesolimbic dopamine reward circuitry.Rodents and the DAT have been observed to interact similarly. Unlike their wildtype littermates, DAT-knockout mice do not experience wakefulness-enhancing effects from modafinil.
Its arousal-enhancing qualities may be explained by its modest DAT inhibitory activity, which has been shown to indirectly stimulate the release of histamine and orexin neuropeptides from the lateral hypothalamus and tuberomammillary nucleus.
Modafinil’s Effects on Behavior
The effects of modafinil on working memory, attention, depression, locomotor activity, and exploratory behavior will all be discussed in this section. Finally, some data demonstrating the potentially addictive qualities of modafinil will be discussed.
Impacts on Inquiry-Based Behavior
Young et al. (2011) used mice to study the dose-dependent effects of modafinil on exploratory behavior. In C57BL/6J and 129/SJ mice, they discovered that modafinil (32, 64, and 128 mg/kg) dramatically increased spontaneous activity, rearing (specific exploration), and the smoothness of locomotor pathways.
The researchers discovered that whereas DRD4 receptors mediated modafinil’s effects on selective exploration, DRD1 receptors were primarily responsible for the drug’s effects on spontaneous exploration in dopamine receptor knockout mice (DRD1-4 mutant mice). The researchers hypothesize that elevated synaptic dopamine and secondary actions mediated by DRD1 and DRD4 receptors may be the cause of modafinil’s effects on exploratory behavior.
Impacts on Motor Functions
Rats’ anterior hypothalamus has been shown to emit more histamine, which may contribute to modafinil’s arousal-promoting effects. This area releases histamine in a way that is strongly associated with locomotor activity, especially in the dark when rats are most active. In light of this, Ishizuka et al.’s 2008 study looked at the impact of modafinil on rats’ locomotor activity in their own cage. The researchers used in vivo microdialysis to detect hypothalamic histamine release in order to examine the role of histaminergic systems.
Ishizuka et al. observed a significant increase in histamine release and locomotor activity at 75 and 150 mg/kg of modafinil. It was discovered that the behavioral effects of 3 mg/kg of methylphenidate and 150 mg/kg of modafinil were comparable. The researchers depleted the rats’ neuronal histamine by administering α-fluoromethylhistidine, an irreversible inhibitor of histamine synthesis, in order to better understand the effects of histamine on locomotor activity. They discovered that whereas methylphenidate stimulation remained unaffected, this totally eliminated modafinil’s ability to enhance locomotor activity. In conclusion, they imply that central histaminergic systems play a crucial role in the augmentation of locomotor activity brought about by modafinil, but not by methylphenidate.
Impacts on Retention
We will review the effects of modafinil on working memory in mice that are healthy, chronically stressed, and sleep-deprived in this section. It is generally established that stress and sleep deprivation impair an animal’s and human’s ability to use working memory. These mouse models provide information on the interactions between modafinil and circumstances that people with modafinil frequently experience.
Impacts on Healthy Mice’s Working Memory
Using a sequential alternation task, Beracochea et al. investigated the impact of modafinil on working memory in C57BL/6 mice. Different doses of modafinil (8 mg/kg, 32 mg/kg, and 64 mg/kg) were injected as part of a pretest injection, and the researchers measured the impact on delayed spontaneous alternation rates.
When compared to controls, they discovered that 64 mg/kg considerably raised alternation scores, but not 8 mg/kg or 32 mg/kg. In particular, the researchers discovered that 64 mg/kg increased alternation rates mostly at long (60s and 180s) intertrial intervals, leading to a delay-dependent improvement in working memory function. The researchers conclude that modafinil improves working memory in a dose- and delay-dependent manner. When assessed using a four-hole board contraption, these benefits did not extend to exploratory or anxiety-related activities.
Impact on Working Memory in Mice with Chronic Stress
Modafinil increases glucocorticoid release through the adrenal cortex, which may improve psychomotor function and memory. Cortisol in humans and corticosterone in rats are examples of glucocorticoids, which are essential mediators of learning and memory processes.In [12]
Pierard et al. measured plasma corticosterone in persistently stressed mice and investigated the association between modafinil dosage and working memory and psychomotor performance. Modafinil (8, 16, or 32 mg/kg) or a control was given by researchers either with or without chronic stress. The rats were made immobile for 14 days in a row in a Plexiglass tube with intense light exposure for 15 minutes each day. The T-maze was used to assess memory performance through spontaneous alternation.
The 16 mg/kg dose generated the best working memory performance when there was no stress, according to the researchers’ observations. Modafinil dosages of 16 mg/kg and 32 mg/kg both markedly raised corticosterone levels. Nonetheless, there didn’t seem to be any correlation between working memory function and plasma corticosterone levels.
Impact of Sleep Deprivation on Working Memory in Mice
Numerous researchers have looked into the effectiveness of modafinil in correcting cognitive impairment caused by sleep deprivation, given that the medication is beneficial in improving alertness and performance in individuals with sleep disorders.In a 2007 study, modafinil’s effects on sleep-deprived mice’s spatial working memory were examined by Pierard and colleagues. In a T-maze, the researchers evaluated working memory that is dependent on delays through spontaneous alternation behavior.
The researchers employed a unique total sleep deprivation device that was verified by EEG recordings to inflict sleep deprivation. This low-stress, automated device is made up of a water box with two platforms that are always moving above and below the water’s surface. The mouse is compelled to move back and forth every ten seconds in order to stay out of the water.(17)
First, compared to the non-sleep-deprived control group, the researchers discovered that diurnal 10-hour sleep deprivation results in impairments in spatial working memory, as seen by decreased alternation rates.They measured the c-Fos protein in different cerebral zones to investigate how sleep deprivation affects brain function. Lack of sleep reduced the expression of c-Fos in the anterior hypothalamus and supraoptic nucleus, two brain areas implicated in the control of the wake-sleep cycle. Additionally, they discovered decreased c-Fos staining in the memory-related frontal cortex, hippocampus, and amygdala.
how they affect depression
With a prevalence of 17% in the population, depression is one of the most prevalent mental health issues. Mood disorders, sleep issues, decreased cognitive function, psychomotor abnormalities, and suicidal thoughts are some of its hallmarks. Decreased dopaminergic activity is the root cause of many of these symptoms, especially in the mesolimbic and mesocortical systems. As a result, modafinil’s capacity to activate D1 and D2 receptors on the dopaminergic system may help alleviate depression.
In order to do this, modafinil’s antidepressant-like effects were assessed in a mouse model of depression by Mahmoudi et al. in 2014. They also looked at the possibility that the effects were caused by dopaminergic receptors D1 and D2.To find the optimal antidepressant dosage, mice were given several doses of modafinil intraperitoneally (50, 75, and 100 mg/kg). They were then put through the Tail Suspension Test (TST) and/or Open Field Test. To rule out psychostimulant effects that might be responsible for decreases in immobility in the TST, the Open Field Test was carried out.
Dopamine D2 Receptors Allow Modafinil to Exercise Antidepressant Effects
In the experiment’s second phase, the researchers investigated how modafinil’s antidepressant effects relate to the dopaminergic system. During this stage, distinct mouse groups received pretreatments with the D2 receptor antagonists sulpiride (50 mg/kg), haloperidol (0.2 mg/kg), and SCH22390 (0.05 mg/kg), which block the D1 receptor.By obstructing the anti-immobility action in the TST, the mice pretreated with haloperidol and sulpiride reduced the antidepressant effect of modafinil. However, the mice that were given SCH22390 beforehand did not counteract the antidepressant effects, indicating that modafinil exclusively acts by activating the dopamine D2 receptor to produce its antidepressant effects.
Modafinil May Be Used in Addition to Traditional Antidepressants
The experiment’s last stage assessed modafinil’s capacity to enhance the ineffective dosages of the traditional antidepressants imipramine (1 mg/kg), fluoxetine (1 mg/kg), and bupropion (1 mg/kg). By lowering immobility time in TST when compared to the antidepressants alone, they discovered that co-administration of modafinil (50 mg/kg) could enhance the effects of these antidepressants. They conclude by saying that because modafinil amplifies the effects of prescription antidepressants, it might be a useful supplementary therapy for depression.
In summary
Numerous research employing different mouse models have demonstrated the ability of modafinil to impact cognition and behavior. Although the exact mode of action of modafinil is unknown, it seems to include multiple neurotransmitter systems and specifically improve movement via acting on the histaminergic system.
In healthy mice, modafinil dose-dependently enhances working memory. Furthermore, at lower dosages, it seems to improve working memory function in chronically stressed mice, while at larger dosages, it shows to improve memory function and brain activity in mice who are sleep deprived.