Modafinil is known for its wakefulness effects and is prescribed to people with sleep disorders, jet lag, ADHD, and fatigue due to work hours. It is also used by people who need to stay alert for prolonged periods such as students, military personnel, and doctors.
Positron emission tomography with [11C]raclopride and [11C]cocaine measured changes in extracellular dopamine levels and dopamine transporter availability (measured as binding potential) in the brains of 10 healthy male participants.
Modafinil Increases Dopamine Levels in the Brain
Dopamine levels in the striatum have been shown to increase after Buy Modafinil Online administration, suggesting that the wake-promoting effects of this drug are mediated by changes in monoamine neurotransmission. However, the exact mechanisms responsible for these increases have remained unclear. The actions of the dopamine transporter (DAT) and the D1 receptor have been implicated, but it has also been suggested that adrenergic receptors may be involved.
Using [11C]raclopride binding, it has been found that the acute administration of modafinil results in a subtle alteration of extracellular dopamine concentrations within the limbic striatum, with changes correlated with changes in dopamine transporter occupancy. This suggests that dopamine levels in the striatum are increased by modafinil, which is in agreement with previous microdialysis studies.
It was further observed that these modafinil-induced changes in DA levels are associated with increases in the extracellular levels of NE and glutamate. Elevations in NE appear to be due to DAT inhibition and adrenergic receptor activation, while the glutamate changes are most likely related to changes in reuptake or synthesis.
Modafinil Increases Dopamine Levels in the Pituitary
Dopamine is important for arousal and motivation and is thought to be involved in several cognitive processes. Modafinil is a wake-promoting drug that enhances dopamine levels in the brain by blocking dopamine transporters. The drug also appears to increase dopamine levels through the D1R and D2R isoforms, although the exact mechanism of action remains unclear.
In one study, modafinil significantly increased dopamine levels in the pituitary gland when given to rat subjects, and this was correlated with changes in [11C]raclopride binding. The results suggest that the arousal and motivation-promoting effects of modafinil are largely due to dopaminergic mechanisms.
Another study used positron emission tomography (PET) in 10 healthy male participants to measure the acute effects of modafinil on extracellular dopamine and dopamine transporters. Participants received either a placebo or the doses of modafinil that are clinically used (200 or 400 mg, administered orally). PET scans were performed with both [11C]raclopride and [11C]cocaine to show changes in dopamine transporter occupancy.
Modalert 200 mg was found to increase dopamine levels in the nucleus accumbens and to decrease [11C]raclopride binding in the caudate and putamen. Moreover, the results indicated that modafinil induces arousal in mice by activating both D1R and D2R isoforms. Furthermore, the arousal-inducing effects of modafinil were completely blocked in orexin-null mice.
Modafinil Increases Dopamine Levels in the Nucleus accumbens
Modafinil is a racemate with two enantiomers that are equipotent in behavioral effects in mice (reviewed by Robertson and Hellriegel, 2003). The R-enantiomer appears to reach higher plasma concentrations after a single oral dose, reaching 2-4 h after administration, suggesting a longer duration of wake-promoting activity. In contrast, the S-enantiomer has a much lower pharmacokinetic profile and is eliminated from the body after 1-5 h.
Previous studies have shown that c-Fos expression is reduced by modafinil in both the VTA and SNc in rats, suggesting that the dopaminergic system is involved in its wake-promoting effects. However, lesions of VTA dopamine neurons did not block modafinil-induced arousal and lesions of SNc dopamine neurons only resulted in a modest reduction in wakefulness.
In this study, we found that modafinil increased dLight1.1 fluorescence in VTA dopamine neurons and SNc dopamine neurons in both non-lesional and ablated animals. dLight1.1 was also elevated in the caudate nucleus and the nucleus accumbens. These results suggest that modafinil increases dopamine levels in the SNc and the caudate nucleus by inhibiting dopamine transporters (DAT) and increasing dLight1.1 binding.
In addition, we found that the inhibitory effects of modafinil on acetylcholine release were also attenuated by the DAT inhibitor, methylphenidate. Finally, adrenergic blockers such as prazosin or yohimbine significantly reversed the arousal-promoting effects of modafinil.
Modafinil Increases Dopamine Levels in the Hypothalamus
Modafinil increases DA levels in the hypothalamus by competitive binding to dopamine transporters (DAT) and thereby inhibits reuptake. This increase in DA levels induces a dopaminergic wake-promoting tone that may be central to its behavioral effects. It also increases NE, norepinephrine, and 5-HT levels in the brain. However, it does not enhance either electrically evoked or spontaneous 5-HT efflux in frontal cortex synaptosomes, unlike fenfluramine and dopamine itself.
In addition to its dopaminergic effects, modafinil has been shown to increase glutamate release in a concentration-dependent manner. In some studies, the glutamate increase was attributed to inhibition of reuptake by DAT. However, in other studies, modulation of adrenergic mechanisms is responsible for these results. Modafinil increases NE-mediated facilitation of the glutamate synaptic release onto medial prefrontal cortex pyramidal cells, an effect that is blocked by prazosin but not by yohimbine. Read More Blog…
