Increased Dopaminergic Transmission Mediates the Wake-Promoting Effects of CNSStimulants Seiji Nishino, Julie Mao, Raghavan Sampathkumaran, Jeff Sheltonand Emmanuel Mignot
Stanford University School of Medicine, Sleep DisordersCenter, Palo Alto, CA 94304, USA
ABSTRACT
Amphetamine-like stimulants are commonly used to treat sleepiness in narcolepsy.These compounds have little effect on rapid eye movement (REM) sleep-relatedsymptoms such as cataplexy, and antidepressants (monoamine uptake inhibitors) areusually required to treat these symptoms. Although amphetamine-like stimulantsand antidepressants enhance monoaminergic transmission, these compounds arenon-selective for each monoamine, and the exact mechanisms mediating how thesecompounds induce wakefulness and modulate REM sleep is not known. In order toevaluate the relative importance of dopaminergic and noradrenergic transmissionin the mediation of these effects, five dopamine (DA) uptake inhibitors(mazindol, GBR-12909, bupropion, nomifensine and amineptine), two norepinephrine(NE) uptake inhibitors (nisoxetine and desipramine), d-amphetamine, andmodafinil, a non-amphetamine stimulant, were tested in control and narcolepticcanines. All stimulants and dopaminergic uptake inhibitors were found todose-dependently increase wakefulness in control and narcoleptic animals. The invivo potencies of DA uptake inhibitors and modafinil on wake significantlycorrelated with their in vitro affinities to the DA and not the NE transporter.DA uptake inhibitors also moderately reduced REM sleep, but this effect was mostlikely secondary to slow wave sleep (SWS) suppression, since selective DA uptakeinhibitors reduced both REM sleep and SWS proportionally. In contrast, selectiveNE uptake inhibitors had little effect on wakefulness, but potently reduced REMsleep. These results suggest that presynaptic activation of DA transmission iscritical for the pharmacological control of wakefulness, while that of the NEsystem is critical for that of REM sleep regulation. Our results also suggestthat presynaptic activation of DA transmission is a key pharmacological propertymediating the wake-promoting effects of currently available CNS stimulants.