Rapid development of functional tolerance to caffeine-induced seizures in rats.
The concentration and time dependence of caffeine-induced neurotoxicity was determined by infusing rats intravenously with caffeine at a rate of about 5, 12.5, and 25 mg kg-1 min-1 until the onset of generalized seizures which occurred at about 82, 28, and 11 min, respectively. The concentration of caffeine in the serum, brain, and cerebrospinal fluid at onset of seizures increased with decreasing infusion rate; the concentrations of caffeine metabolites were negligible and serum protein binding was not affected by the infusion rate. In another experiment, one group of rats was infused with caffeine for 60 min at about 2.2 mg kg-1 min-1 whereas another group was infused with solvent only. Both groups were then immediately infused with caffeine at about 22 mg kg-1 min-1 until onset of seizures. Caffeine concentrations at that time in serum, brain, and cerebrospinal fluid were significantly higher in the caffeine-pretreated animals than in the solvent-pretreated controls. The same pretreatment 17 hr before the fast infusion of caffeine had no apparent effect on caffeine concentrations at onset of seizures. These results show that functional tolerance to the seizure-inducing effect of caffeine in rats develops within minutes and that it is reversible within hours or less.
Yasuhara
M
M
Department of Pharmaceutics, School of Pharmacy, State University of New York, Amherst 14260.
Levy
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004361:Drug Tolerance; D007700:Kinetics; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012640:Seizures / Q000139:chemically induced*; D013805:Theobromine / Q000378:metabolism; D013806:Theophylline / Q000378:metabolism
D002110:Caffeine; D013806:Theophylline; D013805:Theobromine