Psycho-Babble Medication Thread 841206

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Provigil- an unequivocal study revealing mechanism

Posted by zeugma on July 21, 2008, at 8:10:15

Provigil's mechanism has been debated. A PET study in rhesus monkeys from two years ago revealed moderate (35%) occupancy of the dopamine transporter following a dosage that is therapeutic in humans (5 mg/kg). While convincing evidence that Provigil attained part of its effect via this transporter (which already was inferred from its inefficacy in DAT-null mice) it still left open some debate as to dose-equivalency between Macaca mulatta and humans, as well as between po and iv adminstration routes (in that PET study iv adminstration was used).
In the meantime, at least two other studies surfaced claiming alternate mechanisms as provigil's primary one (Korotkova's theory that Provigil is a direct D2 agonist, and eminent neuroscientist's Llinas' theory that electrical coupling via GABAergic interneurons was the mechanism for wake promotion). While both of these theorists have identified mechanisms of the drug, it is likely that these are secondary mechanisms.
This study is unequivocal, confirming the results of the Harvard study using primates (it also allows us to infer that Provigil is more potent in humans than in other primates, giving a sense of dose-equivalences across species):
http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/49/MeetingAbstracts_1/38P

Evidence that modafinil blocks the brain dopamine transporter and decreases dopamine D2 receptor availability in humans
Joanna Fowler1, N. Volkow2, G. Wang1, F. Telang3 and J. Logan1
1 Brookhaven National Laboratory, Upton, New York; ; 2 NIDA, Bethesda, Maryland; ; 3 NIAAA, Bethesda, Maryland

Objectives: Modafinil is a wake-promoting drug used to treat narcolepsy and under investigation for treating ADHD and stimulant addiction. Though there is evidence that the mechanisms of action of modafinil differ from those of stimulants like amphetamine and methylphenidate, which interact with dopamine transporters (DAT) elevating synaptic dopamine (DA) (Lin et al., 1996), a recent study reported significant blockade of DAT by modafinil (iv) in the baboon (Madras et al., 2006). Here we measured the effect of a therapeutic dose of modafinil on DAT and on extracellular DA in the human brain.

Methods: Five healthy males (age 32±5.2) were scanned twice with [11C]cocaine to measure DAT at baseline and 2 hours after modafinil (200 mg po) to assess DAT blockade. One week later, subjects were scanned with [11C]raclopride (D2 receptor radiotracer which is sensitive to changes in DA) before and after modafinil. We used the distribution volume ratio in striatum to that in cerebellum minus 1 (DVR-1) to estimate DAT and D2 receptor availability (Logan et al., 1990).

Results: Modafinil significantly blocked DAT in caudate (49.03±16.8%; p<0.005) and putamen (43.5±15.3%; p<0.004) and increased extracellular DA in striatum as evidenced by decreases in [11C]raclopride binding in caudate (5.3%± 3.23; p<0.02) and putamen (6.1%±2.7; p<0.006).

Conclusions: The levels of DAT blockade and DA increases after a therapeutic dose of modafinil are equivalent to those observed after therapeutic doses of methylphenidate, suggesting that DA enhancing mechanisms are relevant in the therapeutic effects of modafinil. Since drugs that increase DA have the potential for abuse these findings also raise concerns about the abuse liability of modafinil.


 

Re: Provigil- an unequivocal study revealing mecha

Posted by dbc on July 21, 2008, at 13:47:14

In reply to Provigil- an unequivocal study revealing mechanism, posted by zeugma on July 21, 2008, at 8:10:15

Thats very odd considering the first hand accounts i've read of provigil use. Have a direct DA blockade just sounds odd, it must some how bypass a good portion of the reward system. I've never heard any first hand accounts comparing it to MPD or AMP. But rather a more casual activating effect.

 

Re: Provigil- an unequivocal study revealing mechanism » zeugma

Posted by seldomseen on July 21, 2008, at 19:08:29

In reply to Provigil- an unequivocal study revealing mechanism, posted by zeugma on July 21, 2008, at 8:10:15

I'm wary of meeting abstracts as they typically haven't gone through the same peer review as a manuscript has.
Seldom

 

Thanks Zeugma.. very interesting ! (nm)

Posted by Marty on July 22, 2008, at 0:21:15

In reply to Provigil- an unequivocal study revealing mechanism, posted by zeugma on July 21, 2008, at 8:10:15

 

Re: Provigil-to SS, dbc,M

Posted by zeugma on July 22, 2008, at 12:20:16

In reply to Re: Provigil- an unequivocal study revealing mechanism » zeugma, posted by seldomseen on July 21, 2008, at 19:08:29

> I'm wary of meeting abstracts as they typically haven't gone through the same peer review as a manuscript has.
> Seldom

I hope they fix the mistake as to the species used in the Madras et al. study- Macaca mulatta (rhesus monkeys), not baboons.
The reason I find this abstract credible is because it is consistent with well-validated models of animal wakefulness- i.e., DAT inhibition is one mechanism identified as causing increased levels of waking except in DAT-null mice. Also, the numbers seem right- if c.50% occupation of DAT is necessary for strongly wakefulness promoting effects, and 8 mg/kg is the standard dose used iv to increase wakefulness in rhesus monkeys(DAT occupation in Madras' study was 56%), then that correlates well with the results of this study, using the standard dose used against narcolepsy in humans.
Also, in Wisor's 2001 study, modafinil and d-amphetamine increased DA levels to equal amounts in the caudate of narcoleptic dogs.
But the peer-reviewed manuscript will provide stronger empirical evidence.

dbc, I have taken both MPD and modafinil and the two drugs are totally unlike subjectively.MPD I have always thought worked more on recognition memory than modafinil- and has a more pro-emotional effect, leading me to think it worked on mesolimbic circuitry. Modafinil has a more detached feeling and does not help with detail perception or recognition memory. Modafinil helps with spatial awareness, which I always thought was a mesocortical effect.

M, you're welcome! And thanks for all replies.


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