Posted by SLS on August 29, 2001, at 19:30:42
In reply to Re: Edronax - had it ! » JohnL, posted by SalArmy4me on August 29, 2001, at 15:54:02
> How can you prove that adrafinil works on norepinephrine?
Hi Sal.I have not found anything of substance to prove that adrafinil or modafinil have any effect on NE (norepinephrine) reuptake or that they act as ligands of any NE receptor. Just about everything ever written about these drugs refer to the earliest studies that concluded they were agonists at the NE alpha-1 receptor. I bet if you were to look at the bibliographies of all of the recently published studies, you would find them all referring to one or two papers.
A friend of mine is a rather bright biochemist who has frequented psychotropic oriented symposia for the last ten years or so. Two or three years ago, he had the opportunity to speak directly with a principal R&D man who claimed to have helped to develop adrafinil. The pharmacologist told him that the earliest work establishing adrafinil and modafinil as NE alpha-1 agonists was in his words a "red-herring". The studies were wrong.
Last year, while surveying the abstracts on Medline, I discovered that some of the geniuses who were responsible for perpetuating this misinformation made a glaring mistake of logic in drawing their conclusions. They were able to demonstrate that prazosin, a NE alpha-1 antagonist, was capable of preventing or reversing some of the activating effects of modafinil in the lab. Unfortunately, the only thing this observation really proved is that the effects being studied required that these NE neurons be intact. That's all. And I ain't no genius. For all they knew, the therapeutic effects of modafinil might have been produced by tickling the funny-bone of the left arm - as long as those neurons along the way functioned properly.
There must be a significant difference in the pharmacology of adrafinil and modafinil, even though the majority of adrafinil is quickly metabolized into modafinil in the body. John and others who have tried both have described unequivocal differences in the way these drugs effected them. Because there is a paucity of information about adrafinil to be found on Medline, I find it more difficult to rule-out the possibility that something else might be going on there. Both drugs rather potently increase the concentration of extracellular glutamate in various areas of the brain. I am guessing that it is the stimulation of hypothalamic glutamatergic pathways that is responsible for the promotion of wakefulness. The pro-motivational effects might be produced by increasing glutamatergic activity at sites in the thalamus and hippocampus (the land upon which a college for water-horses is established), probably via efferents (inhibition of GABAergic?) to dopaminergic neurons in the nucleus accumbens.
Give the scientists a few more days. Maybe they'll change their minds again. In the meantime, I would not develop any hypotheses that rely upon the supposition that adrafinil and modafinil are agonists of the NE alpha-1 receptor.
I don't know why the hell I wrote all of that. Nothing good on TV.
- Scott
poster:SLS
thread:76755
URL: http://www.dr-bob.org/babble/20010828/msgs/76882.html