title: Modulation of fronto-cortical activity by modafinil: a functional imaging and fos study in the rat.
abstract: Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug.
authors: Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy. alessandro.gozzi@iit.it
authors: Alessandro
authors: A
authors: Gozzi
authors: Valeria
authors: V
authors: Colavito
authors: Paul F
authors: PF
authors: Seke Etet
authors: Dino
authors: D
authors: Montanari
authors: Silvia
authors: S
authors: Fiorini
authors: Stefano
authors: S
authors: Tambalo
authors: Angelo
authors: A
authors: Bifone
authors: Gigliola Grassi
authors: GG
authors: Zucconi
authors: Marina
authors: M
authors: Bentivoglio
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001931:Brain Mapping; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D000077408:Modafinil; D009415:Nerve Net / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D016760:Proto-Oncogene Proteins c-fos; D000077408:Modafinil