ABSTRACT
Central Nervous System (CNS) stimulants used in sleep medicine include amphetamine-like compounds (l-and d-amphetamine and methamphetamine, methylphenidate, pemoline), mazindol, modafinil, some antidepressants with stimulant properties (e.g., buproprion) and caffeine. The effects of most of these drugs on wakefulness is primarily mediated via an inhibition of dopamine reuptake/transport and in some cases, via increased dopamine release. An exception is caffeine, a compound with adenosine receptor antagonistic effects. Biogenic amine transporters [for dopamine (DA), norepinephrine (NE), and serotonin] are located at nerve terminals and are important in terminating transmitter action and maintaining transmitter homeostasis. In the past decade, monoamine transporters have been cloned and their molecular mechanisms have been elucidated and genetically engineered mice lacking these molecules (knockout mice) have also become available. In parallel with these discoveries, potent and selective ligands for the DA and NE transporters have been developed. The results of pharmacological studies using these new ligands in canines and knockout mice models suggest the importance of the DA transporter (as opposed to the adrenergic transporter) for the mode of action of amphetamines, amphetamine-like compounds and bupropion on wakefulness. Importantly, however, the various stimulants also have differential effects on dopamine storage (via VMAT inhibition) or release (and in most cases) have effects on other monoaminergic systems. The mode of action of modafinil, a more recent compound used as a first line treatment for excessive daytime sleepiness (EDS), is controversial. Dopamine reuptake inhibition may also be critical in modafinil’s primary mechanism of action.
