"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.[17][18] 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.[19] 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.[20]
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.[21] 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.[22] 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.[23] Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.[23]" mean??
