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March 29, 2006


Jim Pfrommer

Question about possible use and mechanism of action of modafinil in ADD.

If modafinil is a dopamine reuptake inhibitor, wouldn't that ultimately mean that over time of continued administration, dopamine transmission would be down-regulated?

Whenever I teach psychopharmacology, I always emphasize that there are two parts to every time we put a chemical in the body. The first is the direct effects of that chemical upon the various receptors, and the second is the body's response to that first action...

We've always felt that this why SSRI's are not "addicting" and the benzo's are.

Any thoughts?

Richard Petty

Downregulation should only be a theoretical possibility with modafinil. A group from the University of California has recently published a paper in PNAS, where they describe the mechanism by which some drugs may cause downregulation; it involves a G protein coupled receptor-associated sorting protein, nicknamed GASP! It's main function is to degrade D2 receptors after they have responded to dopamine. Modafinil should not modulate GASP, so there should be a low risk of downregulation.
Modafinil may just as easily be doing its work via GABA receptors. But I think that we also need to be careful about attributing all the actions of a drug to actions at receptors alone. An example of what I mean is clozapine, where it remains possible that some of its clinical activity is not derived from its interaction with receptors at all, but rather by modulating cell membrane phospholipid metabolism, that secondarily affects receptors.

You are quite right to emphasize the dynamic interplay between a medicine and the body: the traffic is never in just one direction.

Jim Pfrommer

"Receptors are SO '90's"
has become my one of my newer mantras as I go back over cell membrane metabolism, ion channels, second messengers, and other things that have come into focus just as we thought we were figuring something out.

Richard Petty

One of the puzzles about the neurochemistry of schizophrenia and bipoar disorder is the number of unconnected neuronal pathways effected. However, each on of the systems has receptors whose characteristics are modulated by changes in cell membrane fluidity (CMF). Part of the rationale for the fish oil experiments, and a possible link between hypercholesterolemia and arteriosclerosis: cholesterol-induced changes in CMF increase the response of endothelial and smooth muscle cells to local growth factors.

Then there's Manji's data on the actions of lithium and divalproex, and all the data on different types of membrane disturbance in ADD and autism.

I highly recommend the "Madnes of Adam and Eve," by the late David Horrobin for a discussion of the phospholipid hypothesis of the physical aspect of schiophrenia, and "Phospholipid Spectrum Disorder in Psychiatry."

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