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.

Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain

“…↑ (30mg/kg, when serotonergic neurons killed, guinea pig) (Tanganelli, 1995) ø (1-30 M, rat) (Ferraro, 2001) ↑ (150mg/kg, rat) (Scammell, 2000) ↑↑ (10mg/kg, rat) (Gozzi, 2012) ↑ NMDA R (64mg/kg, rat) attention shifting task with PCP block (Dawson, 2010) ↑ (300mg, rat) (Engber, 1998) ↓ (100mg, human) on executive task (Rasetti, 2010) cingulate cortex ↓ (200mg, human) reaction time task (Minzenberg, 2011) ø NMDA R (125 mg/kg, mouse) (Nguyen, 2011) ø GABA A R (125 mg/kg, mouse) (Nguyen, 2011) pyriform cortex ↑ (150mg/kg, rat) (Scammell, 2000) Brain regions Neuronal activity (Scammell, 2000) ↑ (150 mg/kg, rat) (Ishizuka, 2007) ø (30-60mg ) & ↓ (100 mg via 5HT3R, rat) (Ferraro, 1996(Ferraro, /1997 ↓ (30-300 mg, rat) ↓ (75, 150mg/kg, rat) (Scammell, 2000) posterior hypothalamus ↑ (30-300 mg, rat) ↓ (cat) (Linunpublished) ↑ (100 mg/kg in vivo rat) (Ferraro, 2002) (Ferraro, 1996(Ferraro, /1997 medial preoptic area ↑ (30-300mg, rat) ↓ (30-300mg, rat) ↑ (100 mg/kg in vivo rat) (Ferraro, 2002) Ventro lateral preoptic area ø (75, 150mg/kg), ↓ (300mg/kg, rat) (Scammell, 2000) ↑ (in vitro rat) (Gallopin, 2004) ↑ (300mg/kg, rat) (Engber, 1998) ↑ (64mg/kg, mouse) (Pierard, 2007) ↑↑ (1, 2.5, 5mg/kg cat) (Lin, 1996) ↓ (100 &300mg, rat) (Ferraro, 1998) prevention of ↓, (100mg/kg, rat) (Ueki, 1993) ↑ (10mg/kg, rat) (Gozzi, 2012) ø (100mg, rat) (Ferraro, 1998) ↓ (30-300mg/kg, rat) (Ferraro, 1...…”

“…Increased neuronal activation has generally been identified with modafinil administration in several regions of the cortex in different animals, including mice, rats, cats and humans (Engber et al, 1998;Ghahremani et al, 2011;Gozzi et al, 2012;Hunter et al, 2006;Lin et al, 1996;Minzenberg et al, 2008;Pierard et al, 2007;Scammell et al, 2000;Urbano et al, 2007). Decreased neural activation has also been described in human studies when cognitive tasks were being performed (Minzenberg et al, 2011;Rasetti et al, 2010) or where the study was performed on individuals suffering from narcolepsy (Joo et al, 2008a), The cerebral cortex has shown increased levels of glutamate (Dawson et al, 2010;Touret et al, 1994), noradrenaline (de Saint Hilaire et al, 2001;Tanganelli et al, 1995;Wisor and Eriksson, 2005) and serotonin (de Saint Hilaire et al, 2001;Ferraro et al, 2005Ferraro et al, , 2000Ferraro et al, , 2002 following modafinil, whereas GABA appears to be down-regulated (Ferraro et al, 1997a(Ferraro et al, , 1997bScammell et al, 2000;Tanganelli et al, 1992Tanganelli et al, , 1995.…”

“…Increased neuronal activity has also been observed in the hippocampus after modafinil administration, both in experimental animals and humans (Engber et al, 1998;Gozzi et al, 2012;He et al, 2011;Joo et al, 2008a;Kim et al, 2007;Pierard et al, 2007;Tsanov et al, 2010). Unlike the cerebral cortex, no studies have assessed the effect of modafinil on monoamines, histamine, or orexin.…”

“…increased neuronal activation (Engber et al, 1998;Gozzi et al, 2012;Urbano et al, 2007) and glutamate levels and decrease of GABA levels (Ferraro et al, 1997a). One study in monkeys showed that noradrenaline receptors were recruited by modafinil, but it is not known how these are regulated by the drug (Madras et al, 2006).…”

“…Striatum. Modafinil increased neuronal activity in the striatum (Gozzi et al, 2012;Lin et al, 1996;Scammell et al, 2000). It also increased levels of dopamine (Aguirre et al, 1999;Andersen et al, 2010;Fuxe et al, 1992;Madras et al, 2006;Nguyen et al, 2011;Ueki et al, 1993;Volkow et al, 2009;Wisor and Eriksson, 2005;Xiao et al, 2004), with one study showing that differential effects of modafinil were obtained, depending on the receptor targeted; D2 receptors were down-regulated by the drug and DAT and D1 receptors up-regulated (Nguyen et al, 2011).…”