Posted by SLS on October 4, 2006, at 6:14:16
In reply to Re: Nicotine and Depression » SLS, posted by florence on October 4, 2006, at 1:28:37
Hi Florence.
> > The mistake that I see often made in the interpretation of such studies is that they are demonstrating that a system must be intact for a drug to work. It does not demonstrate that that system is the site of action of the drug. That was the mistake made with Provigil (modafinil) and NE alpha-1 receptors.
> Scott, could you explain the mistake with Provigil and NE alpha-1 receptors or give me a link Thanks...Florence
In the early 1990s, several investigators pronounced that modafinil produced increased alertness and vigilence via the direct stimulation of central NE alpha-1 receptors and that it was thus a ligand agonist. They based this conclusion on the observation that the increase in locomotor activity seen in mice when modafinil was applied was reversed by prazosin, a NE alpha-1 antagonist. This was an inappropriate conclusion. At most, this only demonstrated that pathways containing NE alpha-1 receptors needed to be intact for modafinil to exert its locomotor properties.
For what it is worth, around the year 2000, a friend of mine met with one of the developers of adrafinil and modafinil at a conference. The developer confirmed that the conclusion by investigators had been incorrect, and that the exact mechanisms of drug had not been worked out. However, by that time they had already been looking at glutamate and hypocretin. Now, I believe much of the focus is on hypocretin and the hypothalamus, although it does promote the release of glutamate in the thalamus.
The manufacturer's label goes out of its way to explain the historic error:
"Modafinil does not appear to be a direct or indirect alpha-adrenergic agonist. Although modafinil-induced wakefulness can be attenuated by the a1-adrenergic receptor antagonist, prazosin, in assay systems known to be responsive to a1-adrenergic agonists, modafinil has no activity."
http://www.rxlist.com/cgi/generic2/modafinil_cp.htm
- Scott
poster:SLS
thread:686441
URL: http://www.dr-bob.org/babble/20061003/msgs/691715.html