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Re: more modafinil perplexities SLS

Posted by zeugma on April 22, 2006, at 20:51:40

In reply to Re: more modafinil perplexities, posted by SLS on April 21, 2006, at 7:50:35

That's interesting. However, binding to a transporter does not guarantee that it will act as a reuptake inhibitor. Mazindol is an example of this at the DAT.>>

If I am not mistaken mazindol is sometimes used as a ligand for the NET. Has mazindol been researched in depression?

Do you think such a hybrid would be helpful in the treatment of depression? What about in your situation?

I have gotten what seems to be an antidepressant effect from provigil at times. It is difficult to isolate a given drug's effect when taking multiple psychotropics. But certainly, from the binding profile alone of the hybrid (subnamolar potency at the NET; nanomolar potency at the DAT) it might be useful as a stimulating AD.

I am amazed that there is still so much uncertainty regarding the mechanism(s) of action of modafinil.

NE alpha-1 activation
DAT inhibition
glutamate release
hypocretin release

I thought the first two had been disproved

There is a researcher at NYU named Stone, who claims to have observed a partial agonist effect of modafinil at alpha-1B receptors. but he admits that his observations are provisional. He is doing extensive research on alpha-1 receptors in depression. He focuses especially on the role that epinephrine, as distinct from NE, plays in the etiology of depressive states.

on the other hand, a study of DAT knockout rodents found that these animals were insensitive to the stimulating effects of modafinil and methamphetamine, but were normally responsive to the locomotor stimulating effects of caffeine. They took this to imply that modafinil in fact gets its effects from the DAT.

It is interesting that both Stone and the researchers who conducted the studies on modafinil and DAT KO animals concede that modafinil is a low-affinity ligand at each receptor, but still gets significant behavioral effects. The studies on modafinil and glutamate/GABA are convincing, but there is no mechanism yet observed to account for its effects on amino acid transmission. OTOH, a direct effect was observed on modafinil's effect on the preoptic area (inhibition of NE reuptake), so this must be a region-specific effect- modafinil's affinity for the NET is much lower than its weak affinty for the DAT. And yet the effect was quite convincing:

Sleep. 2004 Feb 1;27(1):19-25.

Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.

Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P.

UMR 5167 CNRS, Physio-Pathologie des Reseaux Neuronaux du Cycle Veille-Sommeil, Institut Federatif des Neurosciences de Lyon (IFNL, IFR19), Universite Claude Bernard Lyon I, Lyon, France.

STUDY OBJECTIVES: The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. MEASUREMENTS AND RESULTS: Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. CONCLUSIONS: These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

I find modafinil to be much unlike either Ritalin or conventional NET inhibitors. Perhaps its effect is most similar to that of Cylert, which itself has a poorly defined mechanism of action.





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