Modafinil: Not so novel a mechanism

Modafinil, the relatively new stimulant drug for treating narcolepsy has gained popularity in the "cosmetic pharmacology" realm as a wakefulness agent in normal people. Basically, people have been experimenting with it as an alternative to caffeine and amphetamines to feel more alert and counteract the effects of sleep deprivation. Most of the studies and feedback I've come across have demonstrated that it doesn't have many benefits over plain old caffeine. This most recent study demonstrates that the mechanism of modafinil might be more similar to something like amphetamine or ritalin rather than something particularly elusive and novel. Yet, if it the below study is true and modafinil does show good occupancy of the dopamine transporters during treatment, it woudln't explain the supposed lack of abuse potential that modafanil has:

J Pharmacol Exp Ther. 2006 Aug 2
Modafinil Occupies Dopamine and Norepinephrine Transporters in vivo and Modulates the Transporters and Trace Amine Activity in vitro.Madras BK, Xie Z, Lin Z, Jassen AJ, Panas H, Lynch L, Johnson RS, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ.
Harvard Medical School.

Objectives: Modafinil (2-[(diphenylmethyl) sulphinyl]acetamide), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by PET imaging, and in vitro, modafinil activity at the DAT, NET, SERT and rhesus monkey trace amine receptor 1 (TA1). Methods: In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]CFT and of thalamic NET by [(11)C]MeNER. In vitro, modafinil effects in DAT-HEK, NET-HEK and SERT-HEK cells were investigated alone or combined with the TA1 receptor, a Gs-linked receptor that responds to monoamines, including PEA. Results: Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%; n = 4; 8 mg/kg: 54 +/- 3%; n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.6%, n = 6; 8 mg/kg: 56% n = 1). In vitro, modafinil inhibited [(3)H]dopamine (IC50: 6.4 microM), [(3)H]norepinephrine (IC50: 35.6 microM), and [(3)H]serotonin (IC50:> 500 microM) transport via the human DAT, NET, SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but augmented a monoamine transporter-dependent enhancement of PEA activation of TA1 in TA1-DAT or TA1-NET cells, but not TA1-SERT cells. Conclusion: The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.

PMID: 16885432