Modafinil is a stimulant used by some professionals to improve their cognitive performance, especially in the case of long shifts. However, it has several adverse effects that could cause problems in the long run.
Modafinil increases synaptic DA in the thalamus, hypothalamus, and striatum through inhibition of the DA active transporter (DAAT). This effect is abolished by prazosin but not by the adrenergic antagonist yohimbine.
Modafinil binds to the DAT
Modafinil Australia is a psychostimulant that differs from amphetamine in structure and neurochemical profile. It has been shown to directly bind to the DAT with modest potency and to inhibit its uptake with greater potency. It also binds to the NET with less potency.
Its binding to the DAT has been implicated in its actions on several central neurotransmitter systems, with significant effects on DA and NE levels and lesser or no effects on 5HT, glutamate, or HA. Modafinil also increases extracellular adrenergic histamine release in the neocortex, with minimal or no effects on orexin release.
Modafinil augmentation of SSRI therapy has been shown to improve attention and inhibitory control in patients with major depressive disorder. In addition, studies using the Pauli Test have found that modafinil improves performance on a simple arithmetic task in medication-free narcoleptic patients and correlates with decreased the and d power on EEG in the frontal and anterior cingulate cortices.
The clinical efficacy of modafinil in narcolepsy, which is associated with severe hypodopaminergic deficits in the brain, suggests that this drug may act through the orexin system.
Modafinil has been shown to increase Fos-immunoreactivity in identified orexin cells in the perifornical area of the brains of awake mice and rats, and it induces wakefulness more potently in orexin neurons ablated narcoleptic animals than in wild-type mice. Furthermore, modafinil prevents the effect of glutamate cytotoxicity on the reduction of GABA release in cultured cortical neurons.
Modafinil reduces potential at the DAT and the DA receptors
Modafinil does not affect extracellular DA or 5-HT concentrations but reduces the potential for these neurotransmitters to act at the DAT and the DA receptors. In addition, the vigilance-promoting drug also appears to reduce extracellular GABA in the brainstem (de Saint Hilaire et al, 2004). Interestingly, modafinil does not decrease acetylcholine levels in the cortex and does not reverse the scopolamine-induced increase in omission errors in a multiple-choice reaction time test, as does physostigmine.
Modalert Tablet increases Fos-immunoreactivity in orexinergic neurons in the perifornical area, suggesting that this system is involved in its wake-promoting effects. However, the drug fails to increase orexin receptor binding in orexin-deficient narcoleptic dogs (Wisor et al, 2002). It also retains effects on extracellular striatal DA and 5-HT and cognitive performance in orexin 1 receptor-deficient narcoleptic mice, although the magnitude of these effects may be reduced compared to wild-type animals.
In a study of healthy, non-sleep-deprived adults, modafinil enhanced performance on tests of digit span, visual recognition memory, spatial planning, and SSRT. These effects may be mediated through modulation of cortical HA activity, but also by interaction with acetylcholine and the DAT.
Modafinil reduces potential at the DA receptors and the DAT
Modafinil is an extremely effective wake-promoting drug, but it does not have many of the cognitive-enhancing effects seen with some other agents. One of the most notable exceptions is its ability to improve cognition in narcolepsy, a disorder with severe deficiency of hypocretin (orexin).
Modafinil increases Fos-immunoreactivity in identified orexin cells in the perifornical region of the brain (Chemelli and McCarthy, 1999), but does not bind the orexin receptors and retains its effects on extracellular striatal DA and vigilance in orexin-knockout mice (Wisor et al, 2001).
At pharmacologically relevant concentrations, modafinil does not bind to cloned DA and NE autoreceptors, and it lacks many of the behavioral and neurochemical properties associated with amphetamines. However, it does increase LC inhibition of the medial PFC pyramidal cells and affects a subset of these neurons in a way that is not blocked by yohimbine or prazosin, suggesting that its actions are related to DAT-inhibited adrenergic mechanisms. It also appears to enhance learning by increasing the frequency of correct responses and decreasing premature responses in a delayed-response task, a result that is not mediated by DA or NE.
Modafinil reduces potential at the DAT and the DA receptors
Modafinil exhibits a relatively modest affinity for the DA transporter (Ki = 3.19 mm) in a rodent brain preparation and does not appear to bind to other monoamine or neuropeptide receptors, nerve membrane ion channels, or second messenger systems. It is eliminated mainly through amide hydrolysis and a small proportion by cytochrome P450-mediated oxidation, with less than 10% of the orally administered dose excreted in urine (Mignot et al, 1994).
Recent studies using scalp electroencephalography and whole-brain imaging suggest that modafinil’s effects on cognitive function are primarily related to its actions on DA and NE neurotransmission, rather than to DAT inhibition.
Modafinil reduces DA currents in LC neurons of the cingulate cortex and medial prefrontal cortex by antagonizing the action of a1B receptors, which increase NE release via DARARs and enhance post-synaptic adrenergic receptor activation (Lin et al, 1996; Duteil et al, 1997).
This appears to be one mechanism for the observed correlation between the Pauli test performance and the fMRI-measured decrease in the power in these areas. Modafinil also potentiates NE neurotransmission in the hypothalamus, which receives innervation from both DA and NE neurons.