POTENTIAL BRAIN NEURONAL TARGETS FOR AMPHETAMINE-INDUCED, METHYLPHENIDATE-INDUCED, AND MODAFINIL-INDUCED WAKEFULNESS, EVIDENCED BY C-FOS IMMUNOCYTOCHEMISTRY IN THE CAT

Much experimental and clinical data suggest that the pharmacological p rofile of modafinil, a newly discovered waking substance, differs from those of amphetamine and methylphenidate, two classical psychostimula nts. The brain targets on which modafinil acts to induce wakefulness, however, remain unknown. A double-blind study using the protooncogene c-fos as experimental marker in the cat was, therefore, carried out to identify the potential target neurons of modafinil and compare them w ith those for amphetamine and methylphenidate. Cats were sacrificed af ter a single oral administration of amphetamine, methylphenidate, or m odafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, r espectively) and brain sections examined for Fos by immunocytochemistr y. Administration of either amphetamine or methylphenidate evoked Fos- like immunoreactivity in a large number of neurons in the striatum and whole cortex, especially in the caudate nucleus and mediofrontal cort ex, which are known to be dopaminergic targets, In contrast, administr ation of modafinil resulted in the labeling of few cells in these stru ctures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas, These results provide evidenc e for the potential brain targets of modafinil, which differ from thos e of amphetamine or methylphenidate, and suggest that modafinil induce s wakefulness by mechanisms distinct from those of the two stimulants.