Potential Brain Neuronal Targets for Amphetamine-, Methylphenidate-, and Modafinil-Induced Wakefulness, Evidenced by c-fos Immunocytochemistry in the Cat

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-11, Vol.93 (24), p.14128-14133
• Main Authors: Lin, Jiang-Sheng, Hou, Yiping, Jouvet, Michel
• Format: Article
• Language: English
• Subjects: Amphetamine - pharmacology; Animals; Benzhydryl Compounds - pharmacology; Biological Sciences; Brain; Brain - drug effects; Brain - physiology; Cats; Caudate nucleus; Cell nucleus; Central Nervous System Stimulants - pharmacology; Dosage; Double-Blind Method; Drugs; Forebrain; Genes, fos - drug effects; Immunohistochemistry; Male; Methylphenidate - pharmacology; Modafinil; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Neuroscience; Oral administration; Organ Specificity; Pharmacology; Placebos; Proto-Oncogene Proteins c-fos - analysis; Proto-Oncogene Proteins c-fos - biosynthesis; Wakefulness; Wakefulness - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.24.14128

Much experimental and clinical data suggest that the pharmacological profile of modafinil, a newly discovered waking substance, differs from those of amphetamine and methylphenidate, two classical psychostimulants. 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 with those for amphetamine and methylphenidate. Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or modafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, respectively) and brain sections examined for Fos by immunocytochemistry. 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 cortex, which are known to be dopaminergic targets. In contrast, administration of modafinil resulted in the labeling of few cells in these structures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas. These results provide evidence for the potential brain targets of modafinil, which differ from those of amphetamine or methylphenidate, and suggest that modafinil induces wakefulness by mechanisms distinct from those of the two stimulants.