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(On flawed methodology and conclusions) SLS

Posted by Questionmark on October 6, 2006, at 2:26:23

In reply to Re: Nicotine and Depression florence, posted by SLS on October 4, 2006, at 6:14:16

I've always wondered about that (when reading some abstract or article/study that draws its conclusions of receptor action of a drug from this sort of over-simplicity)! It just didn't make any sense to come to those conclusions based on that. It never made any sense to me. These guys (with biochemistry and pharmacology Ph.D.s or whatever else) couldn't really be that illogical and naive, could they? So in my own naivete probably, I usually just assume that I'm probably just missing something and they know what they're doing and they know all the other factors for why that methodology works. But reading your post on this really gets me wondering again. Could they really be that illogical?! I mean, it shouldn't be something that difficult for any rational thinking person to identify, if they work in that field. I don't understand it. ARE we missing something?
Goodness no wonder psychiatry is so messed up! The practitioners are getting much of their information from a gross logical error (and monies, pressure, and advertising from the largest corporate sector in the world [or at least in the U.S.]).
But seriously though-- this really concerns me. When I think about it it seems like MANY of our modern theories about neuropharmacology and receptor pharmacology might have been derived from studies using this method. Is it possible that a lot of what we take for granted as being true regarding the receptor pharmacology of different psychiatric drugs is NOT necessarily true or substantiated?? ... This probably isn't the case now that I think about it-- when I try to think of specific examples. But I still wonder for some of them if this is true. What do you think?
This is probably why you get multiple varying pharmacological descriptions of certain drugs, especially the ones with several receptor actions (like some Atypical antipsychotics for instance).

Anyway, I'll stop my rant now. But I'd really like to hear what your and others' specific thoughts are on this.

And I'm glad you mentioned that info about modafinil and NE alpha-1 receptors. I wasn't aware of that. .. Do you know how many times I read that modafinil is an alpha-1 agonist? Many. I always did think it was kind of strange too. Other drugs that stimulate alpha-1 Rs don't promote wakefulness and all that! In fact that action is responsible for some of their side effects!
Man we need more logicians in drug research. There need to be logicians that oversee & supervise these people. Okay i'll stop.

Anyway, great point and thanks for bringing it to our attention.

> > > 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."
> - Scott




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