Modafinil produces a unique spectrum of pharmacological effects including enhanced vigilance, arousal, and wakefulness in human subjects (Bastuji and Jouvet 1988). The drug is widely used to treat narcolepsy (Banerjee, Vitiello et al. 2004), but is also effective in Attention Deficit Hyperactivity Disorder (ADHD) (Biederman, Swanson et al. 2005). Notwithstanding the expanding clinical indications for modafinil, the neurochemical mechanisms that produce therapeutic improvement remain unresolved. Pre-clinically, modafinil is a weak inhibitor of the DAT, and displays no affinity for dopamine receptor subtypes (Mignot, Nishino et al. 1994). Further evidence supporting low dopaminergic activity is the low abuse potential of modafinil (Jasinski 2000). Various theories have been proposed as alternative modes of action including enhancement of glutamate release and inhibition of Gamma-aminobutyric acid (GABA) release in various brain regions (Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al. 1999). However, the exact mechanisms of action of modafinil and the principle active metabolite, armodafinil, are unknown. Understanding these mechanisms of action is important in assessing the potential therapeutic role of armodafinil. We will test to see if there are differences in the degree of DAT occupancy and D2 binding of armodafinil compared with that of traditional stimulants.~The main target of typical stimulants in the brain is the dopamine transporter (DAT) (Volkow, Wang et al. 1998). We have an exquisitely sensitive methodology to measure DAT occupancy using C-11 altropane and Positron Emission Tomography (PET) (Fischman, Bonab et al. 2001). Our group has previously documented the central nervous system pharmacokinetics of several psychiatric drugs (including methylphenidate) using similar techniques. (Christian, Livni et al. 1996; Fischman, Bonab et al. 1996; Fischman, Alpert et al. 1997; Salazar and Fischman 1999; Fischman, Alpert et al. 2002; Spencer, Biederman et al. 2006).~Increases in intrasynaptic (extracellular) dopamine concentrations associated with medications are routinely measured by changes in C-11 raclopride binding in PET scans. C-11 raclopride binds to postsynaptic D-2 receptors. If the intrasynaptic concentration of dopamine increases, it competes with raclopride leading to a weaker signal (i.e. decreased raclopride binding to D-2 receptors). After administration of a stimulant, associated increases in intrasynaptic dopamine compete with C-11 raclopride binding in this manner (Volkow, Wang et al. 2002). By using this technology we can document the change in D-2 binding in the intrasynaptic space achieved by armodafinil, and compare it to that achieved by a typical stimulant.~To this end, using two PET ligands (C-11 altropane and C-11 raclopride), this protocol seeks to compare the DAT receptor occupancy and the increased intrasynaptic dopamine produced by armodafinil to previous studies of methylphenidate. This research will provide novel and unique information toward better understanding the mechanisms of action of armodafinil in comparison to those of typical stimulants.
The specific aims of this study are 1) to document the Dopamine Transporter (DAT) receptor occupancy of armodafinil using positron emission tomography (PET) scanning with C-11 altropane as the ligand and 2) to document the increased intrasynaptic dopamine produced by armodafinil using PET scanning with C-11 raclopride as the ligand. We hypothesize that DAT occupancy will be low with armodafinil; less than the DAT occupancy produced by therapeutic doses of methylphenidate. We also hypothesize that increases in intrasynaptic dopamine will be relatively low with armodafinil.