BRAIN REGIONAL SUBSTRATES FOR THE ACTIONS OF THE NOVEL WAKE-PROMOTINGAGENT MODAFINIL IN THE RAT - COMPARISON WITH AMPHETAMINE

Modafinil is a novel wake-promoting compound for which the mechanism a nd sites of action are unknown. We examined the neural substrates in t he brain for the actions of modafinil using 2-deoxyglucose autoradiogr aphy and compared the findings to those obtained with amphetamine. Mod afinil showed a relatively restricted pattern of changes in brain regi onal metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine in creased glucose utilization in all subregions of the hippocampus (subi culum, CA1-CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the cent ral nucleus of the amygdala, but amphetamine had no effect in this reg ion. Brain structures in which amphetamine increased metabolic rate bu t modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, th e ventral tegmental area and the pontine reticular fields. These findi ngs suggest that, while both modafinil and amphetamine promote wakeful ness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Mod afinil also lacks the pronounced effects on the extrapyramidal motor s ystem which are characteristic of amphetamine and other psychomotor st imulants, implying that the effects of modafinil are not mediated by t he dopamine system and that modafinil may selectively increase wakeful ness with fewer side effects. (C) 1998 IBRO. Published by Elsevier Sci ence Ltd.