STUDY OBJECTIVE: Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. DESIGN: We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. RESULTS: Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. CONCLUSIONS: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.
STUDY OBJECTIVE:Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. DESIGN: We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. RESULTS:Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TGmice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. CONCLUSIONS: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.
Authors: Serge Guerreiro; Damien Toulorge; Etienne Hirsch; Marc Marien; Pierre Sokoloff; Patrick P Michel Journal: Mol Pharmacol Date: 2008-07-11 Impact factor: 4.436
Authors: Mariana Raineri; Betina González; Celeste Rivero-Echeto; Javier A Muñiz; María Laura Gutiérrez; Carolina I Ghanem; Jean Lud Cadet; Edgar García-Rill; Francisco J Urbano; Veronica Bisagno Journal: Neurotox Res Date: 2014-09-27 Impact factor: 3.911
Authors: Sandor Kantor; Takatoshi Mochizuki; Stefan N Lops; Brian Ko; Elizabeth Clain; Erika Clark; Mihoko Yamamoto; Thomas E Scammell Journal: Sleep Date: 2013-08-01 Impact factor: 5.849
Authors: Christian R Burgess; Yo Oishi; Takatoshi Mochizuki; John H Peever; Thomas E Scammell Journal: J Neurosci Date: 2013-06-05 Impact factor: 6.167
Authors: Yo Oishi; Rhiannan H Williams; Lindsay Agostinelli; Elda Arrigoni; Patrick M Fuller; Takatoshi Mochizuki; Clifford B Saper; Thomas E Scammell Journal: J Neurosci Date: 2013-06-05 Impact factor: 6.167