PRECLINICAL STUDIES WITH MODAFINIL - EVIDENCE FOR VIGILANCE ENHANCEMENT AND NEUROPROTECTION

Modafinil, which is presently used in the treatment of narcolepsy, ind uces EEG arousal in mammals, including rhesus monkeys and produces beh avioral arousal in mice and rats without the induction of stereo-typed 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 neuro chemical mechanisms of the vigilance promoting actions of modafinil sh ow 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 throu gh 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 cereb ral cortex and the nucleus accumbens, which is dependent upon 5-HT rec eptor activation. Increases of dopamine release in the rat nucleus acc umbens appears to involve the inactivation of a local GABAergic mechan ism. It is postulated that a reduction of GABA release plays a relevan t role in the wakefulness produced by modafinil, especially in view of the strong inhibitory regulation by GABA of the excitatory glutamate pathways.