Neuropharmacology Vo1.29, No.6, pp.599-602, 1990 Printed in Great Britain
0028-3908/gO $3.00+0.00 Pergamon Press plc
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D.G. Klroh, N.L.
Neuropsychiatry Branch; Intramural Research Program; National Institute of Mental Health Neuroscience Center at Saint Elizabethe; 2700 Martin Luther King Jr. Avenue S.E.; Waehingtoa, D.C. 20032 *University of Colorado Health Science8 Center; Departments of Psychiatry and Pharmacology; 4200 East Ninth Avenue; Denver, Colorado 80262 **Division of Clinical Pharmacology and Experimental Therapeutics; University of California School of Medicine; Building 30, Fifth Floor; San Francisco General Hospital Medical Center; 1001 Potrero Avenue; San Francisco, California 94110 U.S.A. (Accepted 18 MUMI
Caffeine was chronically administered in four doses (0, 10, 25, and 50 mg/kg/day) to rats via twice-daily intraperitoneal injections for 30 days. Concentrations of brain tissue monoamines, dopamine (DA), norepinephrine (NE), and serotonin (5HT), and monoamine metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid @VA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5HIAA), were determined. At the 10 mg/kg/day dose, no significant changes were found compared with controls. At 25 mg/kg/day and 50 a&kg/day significant changes were observed within each monoamine system. In striatum, DA and 5HT were increased, while DOPACwas decreased. In frontal cortex, NE was increased. In cerebellum, 5HT and MHPGwere increased. sml4ARY.
Key Words: caffeine; dopamine; norepinephrine; eerotonin
Caffeine, an adenosine receptor antagonist, ie perhaps the most widely consumed drug in our Although a number of investigators have examined the effects of caffeine on brain society. monamines, theae studies have typically used single acute doses or -in vitro modela and have There have been few studies concerning the central generated mixed reeults (Wirsh, 1984). monoaminergic effects of chronic caffeine administration. In the present study, caffeine was administered to rat8 twice-daily for 30 days in order to create an animal model resembling the pattern of caffeine administration commonly encountered in man. t’lKTEIODS 31 male Sprague-Dawley rata weighing 300-350 gm each were After 7 days of acclimation, divided into 4 groups for twice-daily intraperitoneal injections at 8:30-9:30 A.M. and 4:30-5:30 P.M. A control group of 7 rate waa injected with a sterile saline solution. Caffeine (anhydrous, Sigma Chemical, Saint Louis, MO) was given to 8 rata at a dose of 10 mgfkglday, to 8 at 25 mg/kg/day, and to 8 at 50/mg/kg/day, aa solutions in sterile saline. All Kate were weighed twice weekly for injectiona were administered with a total volume of 1 ml. correction of caffeine injection concentrations , maintaining a constant dose in mgfkgfday. Animals were housed in wire cages with food and water provided -ad libitum. Cn the 30th day of caffeine administration (day 29 for controls) each animal waa decapitated 50-60 minutes after injection of the final AM caffeine dose. At the time of sacrifice, core blood was collected in heparinized tubes; plaema was separated and frozen at Caffeine wae measured by gas chromatography -7OOC until aaeay for caffeine concentrations. with a nitrogen phoephorus detector and capillary column, modified from the assay of Jacob, The internal standard was 7-ethyl theophylline. Wilaon, and Benowitz (1981). At sacrifice the brain wa8 quickly removed and placed on ice for diesection. Separate striatum, and lateral cerebellum were diaeeated and tieaue samples from frontal cortex, transferred to pre-weighed conical tubes, immediately frozen, and stored at -70 C until assay. 599
The whole tissue concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (WA), norepinephrine (NE), %methoxy-4-hydroxyphenylglycol (MHPG), serotonin (5HT). and 5-hydroxyindoleacetic acid (SHIAA) were determined using high-performance liquid chromatography coupled with electrochemical detection (Hell, Hoffer and Gerhardt, 1989). Data were analyzed for each monoamine and metabolite in individual brain regions using an analysis of variance (ANOVA). In those cases where the ANOVAindicated a significant difference (p