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Re: provigil mechanism of action?

Posted by SLS on March 1, 2006, at 7:17:55

In reply to Re: provigil mechanism of action?, posted by mike99 on February 28, 2006, at 21:18:59

> > Hi.
> >
> > Provigil (modafinil) seems to possess at least two properties that can increase wakefulness and vigilence:
> >
> > 1. Glutamate release
> > 2. Orexin (hypocretin) release
> >
> >>
> > - Scott
> Glutamate toxicity is currently a hot topic in cognitive dysfunction (there are claims that excess glutamate may be neurotoxic and involved in disorders such as ADHD, Dementia, Alzheimer's...) In fact if I'm not mistaken there's a class of drugs in development called ampakines which antagonize the effects of glutamate. They're experimental for ADHD Dementia and many other cognitive disorders.
> In fact, memantine/namenda is thought to possibly delay the progression or at least treat symptoms of moderate to severe alzheimers by blocking the actions of glutamate (by acting as an NMDA receptor antagonist).
> Just wondering if neurotoxicity would be a potential side effect of provigil and if so whether this would be clinically relevant?

I really don't know. It has been a long time since I looked at that stuff. It might depend on where the glutamate is found and whether the increased levels produce excessive calcium influx.

Most of the excitatory neurons in the brain use glutamate as their neurotransmitter. Glutamate should not be made to look like a scourge. You can't live without it. That a drug like modafinil raises levels of extracellular glutamate might not necessarily translate to neurotoxicity. I haven't really studied this issue well enough to speak with confidence.

Interestingly, some regions of the brain demonstrate overactivity in depression. Perhaps glutamate antagonists help to reduce this.

- Scott




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