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_1/38PEvidence 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, MarylandObjectives: 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.
poster:zeugma
thread:841206
URL: http://www.dr-bob.org/babble/20080718/msgs/841206.html