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 stereotyped behaviors. Pharmacological analysis suggests an indirect involvement of central alpha(1)-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 monoamides. 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. Modafinil has also been shown to produce neuroprotective effects in three different types of lesion models, namely a neurotoxic model with MPTP (parkinsonian model), a mechanical trauma model involving partial hemitransection at the di-and telencephalic level, acid a local ischemia model involving ET-1 induced injury. Modafinil will therefore be of clinical relevance not only in sleep disorders but could also find potential applications in the treatment of neurodegenerative diseases such as Parkinson's disease and stroke