Posted by zeugma on February 25, 2006, at 17:42:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
-z
poster:zeugma
thread:612884
URL: http://www.dr-bob.org/babble/20060219/msgs/613267.html