Pharmacology
Despite extensive research into the interaction of modafinil with a large number of neurotransmitter systems, a precise mechanism or set of mechanisms of action remains unclear. It seems that modafinil, like other stimulants, increases the release of monoamines – specifically, the catecholamines norepinephrine and dopamine – from synaptic terminals. However, modafinil also elevates hypothalamic histamine levels, leading some researchers to consider modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant. Evidence in this direction includes the effects of the co-administration of a dopamine antagonist, which is known to decrease the stimulant effect of amphetamine, but does not entirely negate the wakefulness-promoting actions of modafinil.
The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens, noradrenaline in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.
A considered mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons increasing histamine levels there. It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy for which Modafinil is FDA approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil. Additionally, a study looking at orexin-knockout mice, found that not only modafinil promoted wakefulness in these mice but did so even more effectively than in the wild-type mice.
Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven baffling with respect to the better understood mechanisms of stimulants such as cocaine. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission. Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Urbano et al. determined that modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity. Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. Further research by the same group also noted the capacity of the calmodulin kinase II (CaMKII) inhibitor, KN-93, to abolish modafinil's enhancement of electrotonic coupling. They came to the conclusion that modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergicinterneurons and possibly even glutamatergic pyramidal cells. Additionally, Garcia-Rill et al. discovered that modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and the pedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to the thalamus.
Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must to diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner. Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex. This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil's nootropic effects. Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.
Direct links between electrotonic coupling and wakefulness were provided by Beck et al. who showed that administration of modafinil enhanced arousal-specific P13 evoked potentials in a gap-junction dependent manner. Tying into inconclusive effects on monoamine systems, enhanced electrotonic coupling is thought to reduce activity in localized populations of GABAergic neurons whose normal function is to reduce neurotransmitter release in other cells. For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of decreased GABAergic tone. Thus, while modafinil's unique stimulant profile features interactions with monoamine systems, these may very well be downstream events secondary to effects on specific, electrotonically-coupled populations of GABAergic interneurons. It is likely that modafinil's exact pharmacology will feature the interaction of direct effects on electrotonic coupling and various receptor-mediated events.
Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with an IC50 value of 4 μM. Accordingly, it produces locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor (DRI) vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak DRI, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a DRI and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addiction by the authors of the study.
The (R)-enantiomer of modafinil has also recently been found to act as a D2receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue. The (S)-enantiomer is inactive (Ki > 10,000).
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