title: Chronic effects of xanthines on levels of central receptors in mice.
abstract: 1. Chronic ingestion of caffeine causes a significant increase in levels of A1-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABAA receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A1-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A2A-antagonist, caused only an increase in levels of A1-adenosine receptors. Pentoxifylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A1 and A2A-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: D
authors.initials: D
authors.lastname: Shi
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry; D002110:Caffeine / Q000493:pharmacokinetics / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010431:Pentoxifylline / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D011950:Receptors, Cholinergic / Q000187:drug effects; D011955:Receptors, Drug / Q000096:biosynthesis* / Q000235:genetics; D018079:Receptors, GABA / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D013805:Theobromine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D013806:Theophylline / Q000493:pharmacokinetics / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D000697:Central Nervous System Stimulants; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; D011955:Receptors, Drug; D018079:Receptors, GABA; D018047:Receptors, Purinergic P1; D011985:Receptors, Serotonin; D014970:Xanthines; D002110:Caffeine; C057837:3,7-dimethyl-1-propargylxanthine; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine; D010431:Pentoxifylline; D015056:1-Methyl-3-isobutylxanthine