Here you go boo….TLDR…..we ain’t real fucking sure what all Modafinil is fucking with, but it works….
Modafinil has shown the ability to increase HA, NE, 5-HT, and DA levels in the brain (
Ferraro et al 2000;
de Saint Hilaire et al 2001;
Ferraro et al 2002;
Madras et al 2006), but modafinil almost certainly exerts some of these effects in part via an indirect mechanism or an upstream site of action. Though the recent paper by Madras and colleagues indicates that modafinil has some physiologically significant effect on the DAT and possibly the NET, not all of modafinil’s effect are likely mediated by this particular mechanism, as the investigators themselves suggest. In vitro studies indicate that modafinil does not directly stimulate 5-HT release, but it does enhance 5-HT tone from neurons or synaptosomes stimulated via other methods (
Ferraro et al 2000;
Ferraro et al 2001;
Ferraro et al 2005). In vivo studies show anatomically selective neurochemical effects of modafinil on monoaminergic systems (
de Saint Hilaire et al 2001;
Ferraro et al 2002), and, notably, while modafinil increases TMN fos expression (
Scammell et al 2000) and HAergic tone it is not able to exert this effect when administered directly into the TMN (
Ishizuka et al 2003). Additionally, despite the importance of orexin in the maintenance of vigilance, modafinil is capable of promoting wakefulness in the absence of an orexin receptors or orexinergic neurons (
Wisor et al 2001;
Willie et al 2005).
Modafinil’s effects on glutamate appear to be quite varied by brain region. It was shown that modafinil increased extracellular glutamate in the medial preoptic and posterior hypothalamus and that this effect was due to the reduction in GABAergic tone mentioned previously (
Ferraro et al 1996,
1999). In the thalamus and hippocampus modafinil also appeared to increase glutamate levels, but here it did not alter GABA tone (
Ferraro et al 1997a). On the other hand it was observed that modafinil did not significantly increase glutamate in the substantia nigra (except at very high doses), in the striatum, or in the pallidum (
Ferraro et al 1998). The effect of modafinil on cortical glutamate is unclear, as it has been reported that modafinil increases cortical glutamate and that modafinil does not significantly increase cortical glutamate (
Pierard et al 1995;
Bettendorf et al 1996). The possibility that modafinil alters GABA and glutamate synthesis rates was explored as possible explanation of modafinil’s effects, and modafinil exhibited no observable effect on these pathways (
Perez de la Mora et al 1999).
Modafinil’s effects on GABA appear to be more consistent across brain regions than its effects on glutamate. Modafinil does not appear to have much effect on GABA in the thalamus or hippocampus, but GABA levels were reduced by modafinil in most brain regions studied: the cortex, medial preoptic area of the hypothalamus, posterior hypothalamus, nucleus accumbens, pallidum, and striatum, and this effect generally appears to be mediated by serotonin (
Tanganelli et al 1995;
Ferraro et al 1996,
1997a,
b,
1998a, b,
1999). Interestingly, in one of these studies (
Tanganelli et al 1995) destruction of serotonin neurons with a selective neurotoxin, did not simply block modafinil’s GABA inhibiting effects but caused modafinil to increase cortical GABA. It appears that in this study the GABAergic neurons were strongly inhibited by a serotonergic mechanism and weakly stimulated via a noradrenergic pathway. If modafinil enhances neurotransmitter release via increased electrosecretory coupling, then it would be expected that modafinil would enhance GABA release upon removal of the serotonergic inhibitory influence.
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