Orexin
Unlike other neurotransmitters, orexin is produced by a very small number of neurons in a specific brain region called the hypothalamus. They are released during wakefulness and bind to orexin receptors on target neurons. The result is increased activity in these neurons, which promotes wakefulness and alertness. Orexin also stimulates the creation of new neurons in the hippocampus, which is involved in memory and spatial abilities. Blocking the effect of orexin is one way to treat sleep disorders, and dual orexin receptor antagonists (DORAs) are currently in development.
Modafinil 200 increases Fos-immunoreactivity in identified orexin cells of the perifornical cortex of mice and rats and has similar effects in orexin-knockout mice. Furthermore, it enhances extracellular striate dopamine levels and wakefulness-promoting activity in orexin-2 receptor-deficient narcoleptic dogs. Interestingly, Modafinil does not interact with the serotonin transporter or increase striate dopamine levels in animals treated with the monoamine oxidize inhibitor (MAOI).
However, the neurobiological mechanisms by which orexin promotes wakefulness are unclear. Orexin neurons project to various regions of the brain, including the hypothalamus and prefrontal cortex. They receive significant innervations from brainstem adrenergic and catecholamine nuclei. In addition, orexin neurons in the hippocampus have direct connections with prefrontal cortex interneurons that modulate sleep/wake cycles and working memory processes.
Several studies have shown that orexin neurons regulate the amount of sleep that an individual needs. One study, for example, found that orexin knockout mice showed severe fragmentation of wakefulness and a lack of REM sleep in the dark phase of the sleep cycle. In contrast, orexin/ataxin-3;CAG/orexin double-transgenic mice had consolidated bouts of wakefulness and normal amounts of REM sleep in the dark phase of their sleep cycle.
Despite their importance in the regulation of sleep, orexins are also important for regulating mood and cognition. A recent study has shown that orexin influences mood by enhancing the creation of new neurons in the hippocampus, a region of the brain associated with memory and spatial abilities. In addition, orexin encourages the release of melatonin and other Modalert Australia sleep-promoting substances in the body.
These results suggest that the brain's orexin system plays a central role in mood and cognitive function and that alterations in this system may contribute to sleep disorders such as narcolepsy.
