Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice.
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.


METHODS
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.
Okuro
Masashi
M
Sleep and Circadian Neurobiology Laboratory, Stanford University, MSLS Bldg Room P213, 1201 Welch Road, Palo Alto, CA 94304, USA.
Fujiki
Nobuhiro
N
Kotorii
Nozomu
N
Ishimaru
Yuji
Y
Sokoloff
Pierre
P
Nishino
Seiji
S
D000818:Animals; D000067699:Ataxin-3; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects*; D009290:Narcolepsy / Q000188:drug therapy* / Q000235:genetics; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D012890:Sleep / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology*; D014157:Transcription Factors
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D014157:Transcription Factors; D002110:Caffeine; D013806:Theophylline; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; C021183:1,7-dimethylxanthine; D000077408:Modafinil