Preclinical studies with modafinil. Evidence for vigilance enhancement and neuroprotection

Modafinil, which is presently used in the treatment of narcolepsy, induces EEG arousal in mammals, including rhesus monkeys and produces behavioral arousal in mice and rats without the induction of stereo-typed behaviors. Pharmacological analysis suggests an indirect involvement of central α₁-adrenergic mechanisms but not of dopamine systems in the behavioral activating action of modafinil. Studies on the neurochemical mechanisms of the vigilance promoting actions of modafinil show no or only weak effects on brain monamides. It is of interest that modafinil can increase glutamine synthase mRNA and protein in various brain regions, suggesting an activation of astrocyte metabolism through wakefulness produced by modafinil and leading to energy production. The major neurochemical action of modafinil, however, appears to be a reduction of GABA release in several brain regions, such as the cerebral cortex and the nucleus accumbens, which is dependent upon 5-HT receptor activation. Increases of dopamine release in the rat nucleus accumbens appears to involve the inactivation of a local GABAergic mechanism. It is postulated that a reduction of GABA release plays a relevant role in the wakefulness produced by modafinil, especially in view of the strong inhibitory regulation by GABA of the excitatory glutamate pathways.