title: Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans.
abstract: Caffeine induces locomotor activation by its ability to block adenosine receptors. Caffeine is metabolized to several methylxanthines, with paraxanthine being the main metabolite in humans. In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, theophylline and theobromine. As previously described for caffeine, the locomotor activating doses of paraxanthine more efficiently counteract the locomotor depressant effects of an adenosine A(1) than an adenosine A(2A) receptor agonist. In drug discrimination experiments in rats trained to discriminate a maximal locomotor activating dose of caffeine, paraxanthine, unlike theophylline, generalized poorly to caffeine suggesting the existence of additional mechanisms other than adenosine antagonism in the behavioral effects of paraxanthine. Pretreatment with the nitric oxide inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) reduced the locomotor activating effects of paraxanthine, but not caffeine. On the other hand, pretreatment with the selective cGMP-preferring phosphodiesterase PDE9 inhibitor BAY 73-6691, increased locomotor activity induced by caffeine, but not paraxanthine. Ex vivo experiments demonstrated that paraxanthine, but not caffeine, can induce cGMP accumulation in the rat striatum. Finally, in vivo microdialysis experiments showed that paraxanthine, but not caffeine, significantly increases extracellular levels of dopamine in the dorsolateral striatum, which was blocked by l-NAME. These findings indicate that inhibition of cGMP-preferring PDE is involved in the locomotor activating effects of the acute administration of paraxanthine. The present results demonstrate a unique psychostimulant profile of paraxanthine, which might contribute to the reinforcing effects of caffeine in humans.
authors.affiliation: National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Orrú
authors.forename: Xavier
authors.initials: X
authors.lastname: Guitart
authors.forename: Marzena
authors.initials: M
authors.lastname: Karcz-Kubicha
authors.forename: Marcello
authors.initials: M
authors.lastname: Solinas
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Sandeep Kumar
authors.initials: SK
authors.lastname: Barodia
authors.forename: Janaina
authors.initials: J
authors.lastname: Zanoveli
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortes
authors.forename: Carme
authors.initials: C
authors.lastname: Lluis
authors.forename: Vicent
authors.initials: V
authors.lastname: Casado
authors.forename: F Gerard
authors.initials: FG
authors.lastname: Moeller
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
mesh_terms: D000818:Animals; D002110:Caffeine / Q000378:metabolism* / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000697:Central Nervous System Stimulants; D002110:Caffeine; D013806:Theophylline; C021183:1,7-dimethylxanthine