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PubMed1983

Pre- and postnatal effects of caffeine on brain biogenic amines, cyclic nucleotides and behavior in developing rats.

To examine the perinatal effects of caffeine on pup behavior and brain neurochemistry, rat mothers were exposed to caffeine in a choice situation prenatally, postnatally, at both times or at neither time. Prenatally, caffeine-exposed mothers drank approximately 14 mg/kg/day, an amount ineffective in altering mothers' overall prenatal body weight, although it did reliably decrease birth femur length of offspring. Postnatal pup activity measures revealed that postnatal caffeine exposure depressed activity, with an additional contribution of prenatal caffeine exposure. Those effects occurred at caffeine intake levels (circa 48 mg/kg/day) which minimally affected pup body weight, body length, femur length or eye-opening. Postwithdrawal (35 days of age) biochemical determinations revealed significant postnatal effects of caffeine by depressing cyclic AMP/"whole-brain" and elevating the cyclic GMP/cyclic AMP ratio in cerebellum. Whole-brain levels of dopamine and norepinephrine, however, were not affected by the caffeine treatments. These results suggest that activity profiles may be a more sensitive index of caffeine "toxicity" than other indices of physical development, and that cyclic nucleotides may play at least some role in the hypoactivity-inducing effects of caffeine in developing rats.

Animals↗
PubMed1980

Unit activity in medial thalamus: comparative effects of caffeine an amphetamine.

The effects of caffeine and d-amphetamine sulfate were evaluated upon single unit activity of medial thalamus in chloral hydrate anesthetized rats. Single unit activity recorded extracellularly with platinum-iridium microelectrodes. It was found that caffeine, 0.1 to 0.5 mg/kg i.v., markedly suppressed and that amphetamine, 0.1 to 1 mg/kg i.v., markedly augmented the spontaneous firing rates of medial thalamic neurons. It was also demonstrated that amphetamine was capable of activating the medial thalamic neuronal activity while it was suppressed by caffeine. On the other hand, while the firing rate was increased by a previous amphetamine injection, administration of caffeine suppressed the amphetamine-induced augmentation of neuronal activity. The data imply that these two central nervous system (CNS) stimulants, caffeine and amphetamine, have different mechanisms of action at least at the medial thalamic site. Moreover, since medial thalamus participates in the recruitment phenomenon and exerts a stabilizing action on the cerebral cortex, our findings that caffeine suppressed this brain area suggest that the medial thalamus may be an important site of action for the arousal induced by caffeine. In addition, the demonstration of inhibitory effects of caffeine on the medial thalamus in this study and excitatory effects on brain stem reticular formation from our previous studies indicate that caffeine has differential actions on different brain areas. This observation broadens the generally held belief that caffeine excites at all levels of the CNS to specifically include inhibition of inhibitory influences in at least one functional system of the brain.

Action Potentials↗
PubMed1995

The caffeine- and ryanodine-sensitive Ca++ store in porcine myometrial cells: its heterogeneity of all-or-none Ca++ release.

The mechanisms for Ca++ release from caffeine-sensitive stores were investigated in freshly dispersed porcine myometrial cells utilizing the fura-2 method. Because the caffeine-sensitive Ca++ store has not been detected in myometrium of mammals, we first determined the existence of this type of store in porcine myometrial cells. The evidence includes: 1) caffeine (1-33 mM)-induced concentration-dependent increase in the intracellular Ca++ concentration ([Ca++]i) in both the presence and absence of extracellular Ca++ and 2) although ryanodine alone (< or = 10 microM) failed to change [Ca++]i, it inhibited the response to caffeine in a use-, concentration- and time-dependent manner. In the cell suspension study, the amount of Ca++ released by 10 mM caffeine was found to be inversely proportional to the amount released by preadministration of caffeine (1-33 mM). In the single cell study, about 30% of cells responded to only a certain concentration of caffeine and the others responded to caffeine gradually. Thapsigargin, an inhibitor of Ca(++)-adenosine triphosphatase in sarcoplasmic reticulum, failed to increase [Ca++]i. Pretreatment with thapsigargin inhibited the response to caffeine in a time- and concentration-dependent manner. These results suggest that in porcine myometrial cells: 1) the Ca++ released from the caffeine- and ryanodine-sensitive store is in an all-or-none manner through compartments of stores or the entire store of a cell and 2) the release process is regulated by luminal Ca++ content of the stores.

Animals↗
PubMed1995

The effects of theophylline and caffeine on the isolated rat diaphragm.

It is a well known fact that theophylline enhances the force of diaphragmatic contraction and delays fatigue. The action of caffeine which is a methylxanthine analogue on skeletal muscle are complex. It was claimed in few studies that the caffeine was more effective on the diaphragmatic contractility than the theophylline. The aim of this study is to compare the effects of theophylline and caffeine on the tension generated by fresh and fatigued diaphragmatic muscle. Studies were performed in vitro on diaphragmatic muscle strips of rats activated by electrical stimuli applied via the phrenic nerve. Isometric twitch characteristics (twitch tension, contraction and 1/2 relaxation time) were measured. Force-frequency responses were generated using twitches and tetanic contractions produced by stimulating the phrenic nerve with 0.2 ms pulses at 10, 20, 50 and 100 Hz for 1 s with 30 s intervals. Moderate fatigue was then induced by repeated submaximal contractions (25 Hz, 160 ms, at the rate of 1/s for 45 contractions). In fresh muscle 1 mM theophylline and 1 mM caffeine increased diaphragmatic tension 40.98 +/- 8.50% and 82.30 +/- 12.21% of the initial value respectively. Theophylline did not alter contraction time but prolonged 1/2 relaxation time, whereas caffeine had no effect on any one. Theophylline induced force production in all frequencies. Caffeine caused an increase in force only in < 20 Hz, but a decrease in 50 and 100 Hz. In brief submaximal fatigue, both 1 mM theophylline and 1 mM caffeine partly prevented fatigue (effect of caffeine was more potent). This study suggests that caffeine has a greater effect than theophylline on the muscle. Possible mechanism(s) of action of theophylline and caffeine on diaphragmatic contractility and fatigue were discussed. It may well be the fact that they might have different mechanisms of action on the isolated rat diaphragm.

Animals↗
PubMed1996

Studies on the chronic oral toxicity of an analgesic drug combination consisting of acetylsalicylic acid, paracetamol and caffeine in rats including an electron microscopical evaluation of kidneys.

The analgesic drug combination Thomapyrin consisting of acetylsalicylic acid (CAS 50-78-2, ASA), paracetamol (CAS 103-90-2, NAPAP) and caffeine (CAS 58-08-2) in the ratio 5:4:1 was investigated for its chronic toxicity in rats. For comparison the individual drugs ASA and NAPAP as well as the double combination ASA+NAPAP were tested in equipotent doses. 20 male and 20 female rats per group (Chbb:THOM/SPF) received doses of 50, 100 and 200 mg/kg of the combination ASA+NAPAP+caffeine, 45 and 180 mg/kg of the combination ASA+NAPAP, and 50 and 200 mg/kg of the individual drugs ASA or NAPAP over a period of 6 months. The daily dose was splitted into two parts and administered 3 h apart. The rats were single housed under standardized conditions with free access to food and drinking water. Plasma concentrations were measured in four additional animals of all high dose groups after the last dosing at seven time points. Besides the usual routine toxicological investigations the kidneys of five females per group were investigated by transmission electron microscopy. All investigations were performed according to GLP regulations. All animals behaved unobtrusively throughout the study with only minor impairment of general conditions in some animals of all ASA, ASA+NAPAP+caffeine and the high dose NAPAP groups. Dose related mortality was observed in the groups receiving ASA alone or in combination, partly with rales and tonic convulsions immediately prior to death. Body weight gain was decreased in males but not in females of the ASA+NAPAP+ caffeine and ASA groups. No consistent drug- and dose-dependent changes in hematological, clinico-chemical or urinanalytical parameters were observed, except for a slight increase in excretion of epithelial cells in both genders of the ASA groups. Plasma drug level monitoring demonstrated that the pharmacokinetics of ASA were not altered by co-administration of caffeine or NAPAP or vice versa. In males, maximum plasma concentrations (Cmax) and areas under the curve (AUC) for ASA and NAPAP tended to be slightly lower than in females. The plasma concentrations reached in the study represent a low multiple (2.2-7.9) of therapeutic plasma levels. Therefore, the results reported in the study can be considered representative for normal therapeutic use of the analgesic combination ASA+NAPAP+caffeine. Gastric erosions in the ASA and ASA+NAPAP+caffeine groups, increased kidney weights in females given 200 mg/kg ASA+NAPAP+caffeine, and dose-dependently increased liver weights in females given 200 mg/kg ASA and decreased liver weights in males at 100 and 200 mg/kg ASA-NAPAP+caffeine were the only consistent drug-induced changes observed at necropsy. Except for the above mentioned ulcer, all histopathological findings were iatrogenic or spontaneous lesions. The kidneys demonstrated initial stages of age-associated nephropathy at comparable incidence and severity in all groups including controls. Semi-thin section evaluation and transmission electron microscopy showed only minor changes. Taking all tubular and vascular changes together (total mean), the animals of the NAPAP group were slightly more affected than those of the other groups. Summing up it can be concluded that the nephrotoxic potential of the combination ASA+NAPAP+caffeine, if existing at all, was marginal even after prolonged administration, and that it does not exceed that of the monosubstances when given at pharmacologically equipotent doses and clinically relevant exposures.

Acetaminophen↗
PubMedDate not supplied

Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics.

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC0-infinity) values +/- SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 +/- 10.8, 48.7 +/- 15.2, and 49.6 +/- 7.0 micrograms/ml.hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.

Adult↗
PubMed1997

[Caffeine and children].

Beverages containing caffeine are consumed by most people in most countries most days. Consumption is mostly in beverages such as coffee, tea and some soft drinks, and smaller amounts from other foods such as chocolate. Children also consume caffeine, though in smaller amounts even relative to their smaller size. Many questions have been asked about possible health effects of caffeine and have been answered by scientific research. Studies on pregnant women consuming caffeine show no effects on the fetus, infants, or on development followed up to school age. There have been many studies on children of school age. For example, it has been shown that a single dose of 3 mg/kg is without appreciable effect on a variety of behavioral and physiological functions, and even 10 mg/kg, had only minimal effects, within the normal range of differences between the children without caffeine. While newborn infants metabolize caffeine slowly, children from less than 1 year to adolescence metabolize caffeine about twice as fast as non-smoking adults. The numerous studies showing safety of caffeine in adults, combined with the direct studies in children showing they are similar and not more susceptible to caffeine than adults, gives assurance that lifelong consumption of caffeine in foods and beverages, starting in childhood, is without deleterious effects on health.

Adolescent↗
PubMed1998

Non-destructive analysis of natural variability in bean caffeine content of Laurina coffee.

In order to conserve the germination power of coffee beans, only a tiny portion of endosperm was excised for caffeine determination. These non-destructive, single-bean analyses of the low-caffeine coffee mutant Laurina (C. arabica cv. laurina) revealed (a) a variation of the caffeine content from 0.36 to 1.08%, with lowest values found in the tissue culture-derived genotypes (somaclones), (b) a markedly lower mean caffeine content (0.56-0.61% dry wt) in the somaclones than in the parent line (0.68-0.71%), and (c) a high correlation between the caffeine contents of the bean and cotyledons emerged from it. Hence, breeding for low-caffeine coffee will be facilitated in future by simply analysing the cotyledons for this character. The combination of "somaclones" and single-seed analysis may be a useful and general strategy to tailor the phytochemical pattern of plants.Additionally, the young leaflets of Laurina, equally to the seeds furnished with a low caffeine content, were studied with respect to the N-methyltransferase (NMT) activities catalysing the last two steps in caffeine biosynthesis. The related activities were much lower than of the cultivar Catuai indicating that the lr lr alleles of Laurina, responsible for the reduction in half the "normal" caffeine content, interfere with the synthesis and not with the catabolism of caffeine.

Journal Article↗
PubMed1991

Dose-related caffeine discrimination in normal volunteers: individual differences in subjective effects and self-reported cues.

A within subject design was used to study a caffeine versus placebo drug discrimination in five volunteers who were not explicitly instructed that the drug conditions involved caffeine and placebo. The caffeine (200 or 300mg) versus placebo discrimination was acquired by all subjects and remained stable (78-90% accuracy) throughout the study which spanned 5 to 8.7 months across the subjects. A full caffeine dose-response function (50 to 400 or 600mg) was determined repeatedly under test conditions in each subject; caffeine produced orderly dose-related increases in caffeine identification in all subjects. The present study evaluated individual subject data to examine the correspondence between the subjective effects of caffeine versus placebo and the cues subjects reported as being important to making the discrimination. Although the subjective effects and self-reported cues differed across subjects, there was a correspondence within subjects. Prominent self-reported cues for caffeine included jittery/nervous/anxious (four subjects) and alert/active (one subject); self-reported cues for placebo included tired and/or headache (three subjects) and absence of drug effect (two subjects). The reporting of tired and headache as cues for the placebo condition suggests that caffeine withdrawal may produce stimulus effects relevant to the caffeine versus placebo discrimination.

Journal Article↗
PubMed1993

Pharmacological specificity of the caffeine discriminative stimulus in humans: effects of theophylline, methylphenidate and buspirone.

The present study examined further the pharmacological specificity of the methylxanthine CNS stimulant caffeine as a discriminative stimulus in humans. Nine normal healthy volunteers (ages 19-39) were trained to discriminate between caffeine (320mg/70kg, p.o.) and placebo, using monetary reinforcement of correct letter code identification. After four training sessions, subjects were tested with the training conditions until they were >80% correct on four consecutive sessions. Then dose-effect curves were determined for caffeine (56-320mg/70kg), theophylline (56-320mg/70kg), methylphenidate (10-56mg/70kg), and buspirone (1-32mg/70kg). Seven of nine subjects met the discrimination criterion within four to nine sessions. During dose-effect curve determinations, caffeine and methylphenidate each produced dose-related increases in caffeine-appropriate responding. Theophylline produced caffeine-appropriate responding that was not dose related in a consistent manner across subjects, occasioning an average of 50% caffeine-appropriate responding at most doses tested. Buspirone produced predominantly placebo-appropriate responding. Caffeine-appropriate responding tended to be directly related to ARCI LSD scores, self-reported "bad" effects, "high", and stimulant-bad effects and inversely related to ARCI PCAG scores and sedative ratings. These results agree with non-human data and suggest that the caffeine discriminative stimulus has pharmacological specificity, in that caffeine-appropriate responding generalizes to other stimulants such as theophylline or methylphenidate, but not to non-stimulant compounds such as buspirone.

Journal Article↗
PubMed2004

The association of caffeinated beverages with blood pressure in adolescents.

OBJECTIVE: To assess the association between the consumption of caffeinated beverages and blood pressure in African American and white adolescents. DESIGN: This study was part of ongoing research examining stress-induced hemodynamic responses in adolescents. African American and white adolescents (n = 159) selected foods and beverages for a 3-day sodium-controlled diet. Caffeine in these foods was used to stratify participants into 3 categories (0-50 mg/d, >50-100 mg/d, and >100 mg/d). Before menu selection, blood pressure readings were obtained. STATISTICAL ANALYSIS: A general linear model (multiple regression with both categorical and continuous variables) was developed to assess the effects of race, category of caffeine intake, and interaction of race and caffeine intake on systolic and diastolic blood pressure controlling for sex and body mass index (calculated as weight in kilograms divided by height in meters squared). RESULTS: The association between systolic blood pressure and caffeine category varied by race (P =.001). African Americans consuming more than 100 mg/d of caffeine had higher systolic blood pressure readings than the groups consuming 0 to 50 mg/d (mean difference, 6.0 mm Hg; 95% confidence interval [CI], 2.3 to 9.7) or more than 50 to 100 mg/d (mean difference, 7.1 mm Hg; 95% CI, 3.4 to 10.7). The effect on diastolic blood pressure was less pronounced (P =.08). The diastolic blood pressure of the group consuming more than 100 mg/d was 3.7 mm Hg (95% CI, 0.41 to 7.0) higher than the group consuming more than 50 to 100 mg/d and was not statistically different from the group consuming 0 to 50 mg/d (mean difference, 2.4 mm Hg; 95% CI, -0.9 to 5.8). There was no evidence that the association between diastolic blood pressure and caffeine intake varied by race (P =.80). CONCLUSIONS: For adolescents, especially African American adolescents, caffeine intake may increase blood pressure and thereby increase the risk of hypertension. Alternatively, caffeinated drink consumption may be a marker for dietary and lifestyle practices that together influence blood pressure. Additional research is needed owing to rising rates of adolescent hypertension and soft drink consumption.

Adolescent↗
PubMed1985

The inhibitory effect of caffeine on hormone-induced rat breast cancer.

Studies have associated coffee and/or caffeine with human fibrocystic breast disease. Two animal studies have implicated caffeine as a promoter in rat mammary cancer. The current investigation examines the effect of two caffeine doses in ACI rats with and without diethylstilbestrol (DES). Without DES, cancer did not develop in any of the rats receiving either of the two caffeine dosages. With DES, increasing caffeine dosage lengthened the time to first cancer, decreased the number of rats that developed cancers, and decreased the number of cancers overall. The presence or amount of caffeine did not cause detectable histologic differences in the breast cancers. The presence or amount of caffeine did not influence animal weight or mortality, although the rats without DES weighed more and survived better into old age. The presence or amount of caffeine did not influence pituitary weights and prolactin levels, although values of the DES groups were three times higher than the values for the group without DES (P less than 0.05). In conclusion, chronic caffeine ingestion inhibits rat breast cancer, neither by interfering with the high prolactin levels--a necessary step in murine tumor development--nor by causing hypocaloric intake.

Animals↗
PubMed2000

Caffeine versus theophylline for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Two forms of methylxanthine (caffeine and theophylline) have been used to stimulate breathing and so prevent apnea and its consequences. OBJECTIVES: In preterm infants with recurrent apnea, does caffeine treatment compared to theophylline treatment lead to a clinically important reduction in apnea and use of mechanical ventilation without clinically important side effects? SEARCH STRATEGY: Standard strategies of the Neonatal Review Group were used. Searches were made of the Oxford Database of Perinatal Trials, MEDLINE (see main text for strategy), previous reviews including cross references, abstracts conferences and symposium proceedings, expert informants, journal handsearching mainly in the English language. Also an expert informant's search in the Japanese language was made by Prof Y. Ogawa. SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation in which caffeine was compared with theophylline for the treatment of apnea were eligible. Trial quality and eligibility were assessed independently by each author. There must have been an effort to exclude specific causes of apnea. Measures of the severity of apnea as well as the response to treatment must have been consistent with an evaluation of 'clinical apnea' as defined by the American Academy of Pediatrics (Nelson 1978). DATA COLLECTION AND ANALYSIS: Standard method of Neonatal Review Group was used. Each author assessed eligibility, trial quality and extracted data separately, then compared and resolved differences. Results are expressed as relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) was calculated. MAIN RESULTS: There is no difference in the failure rate (< 50% reduction in apnea/bradycardia) of treatment with caffeine or theophylline at 1-3 (two studies) or 5-7 days (one study). There is a higher mean rate of apnea in the standard caffeine group at 1-3 days [three studies, mean diff. 0.398 (0.334,0.463) /100min] but not at 5-7 days (two studies). Side effects, as indicated by tachycardia or feed intolerance leading to change in dosing, are lower in the caffeine group [typical RR 0.17 (0.04,0.72), RD -0.285 (-0.467,-0.104), NNT 3.5 (2.1, 9.6)]. This was consistent across the three studies. No trial reported the use of IPPV and no data are available to assess effects on growth and development. REVIEWER'S CONCLUSIONS: Caffeine appears to have similar short term effects on apnea/bradycardia to theophylline. In view of the other therapeutic advantages of caffeine (a higher therapeutic ratio, more reliable enteral absorption and a longer half life) this is the preferred treatment for apnea in preterm infants. The possibility that higher doses of caffeine might be more effective in extremely preterm infants needs further evaluation in randomized clinical trials.

Apnea↗
PubMed2005

Multiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers.

UNLABELLED: The purpose of this study was to examine the pharmacokinetics of three doses of caffeine administered as Stay Alert chewing gum in a multiple dose regimen. METHODS: A double-blind, parallel randomized, four-treatment study design was employed. The treatment groups were: 50, 100 and 200 mg caffeine and placebo. Subjects were 48 (n = 12 per group), healthy, non-smoking, males and females who had abstained from caffeine ingestion for at least 20 h prior to dosing, who were randomly assigned to the treatment groups. Caffeine was administered at 2,400, 0200 and 0400 h depending on the treatment group. Blood samples were collected pre-dose and at 5, 15, 30, 45, 60, 75, 90 and 105 min after each caffeine dose. Samples were also collected at 7.5, 8.5 and 18 h after the last dose of caffeine. Plasma caffeine levels were analysed by a validated UV-HPLC method. RESULT: The mean T(max) after the third dosing ranged from 0.37 to 1.12 h. C(max) for 50, 100 and 200 mg was 2.69, 3.45 and 6.33 mg/l, respectively. AUC(inf) for 50, 100 and 200 mg group was 33.2, 46.94 and 86.94 mg/l * h, respectively. AUC(inf) values suggested a dose proportionate increase. Dose normalized C(max) and AUC(0-tau) values across doses were not significantly different, suggesting linearity was maintained after multiple doses of the Stay Alert chewing gum. There were no group related differences in elimination. CONCLUSIONS: The results suggest that caffeine administered in the gum formulation (Stay Alert chewing gum) via a multiple dosing regimen provides an effective and convenient means of maintaining effective concentrations of caffeine that would in some operational scenarios be desirable for maintaining alertness and performance in sleep deprived individuals.

Absorption↗
PubMed1987

Study of deuterium isotope effects on protein binding by gas chromatography/mass spectrometry. Caffeine and deuterated isotopomers.

A study of the binding to human serum albumin (HSA) of caffeine and its deuterated isotopomers, 1-C2H3-,3-C2H3-, 1,7-(C2H3)2-, 3,7-(C2H3)2- and 1,3,7-(C2H3)3-caffeine, was performed by equilibrium dialysis. Free and bound fractions were measured by gas chromatography/mass spectrometry. Important and significant (Fischer and Student tests) isotope effects were observed on binding parameters: sites total concentration (N = 1732 microM for 1,3,7-(C2H3)3-caffeine versus 822 microM for caffeine; number of sites (n = 3 for 1,3,7-(C2H3)3-caffeine v. 1 for caffeine); and extent of binding (46% for 1,3,7-(C2H3)3-caffeine v. 27% for caffeine). A study of competition for HSA binding between caffeine and its 1,3,7-(C2H3)3- and 3,7-(C2H3)2-isotopomers confirmed the results obtained in direct binding studies. These isotope effects are discussed in terms of (a) tools for molecular pharmacology, (b) precautions to be taken when such labelled drugs are used in clinical pharmacology.

Caffeine↗
PubMed2006

Differential c-Fos immunoreactivity in arousal-promoting cell groups following systemic administration of caffeine in rats.

Despite the widespread use of caffeine, the neuronal mechanisms underlying its stimulatory effects are not completely understood. By using c-Fos immunohistochemistry as a marker of neuronal activation, we recently showed that stimulant doses of caffeine activate arousal-promoting hypothalamic orexin (hypocretin) neurons. In the present study, we investigated whether other key neurons of the arousal system are also activated by caffeine, via dual immunostaining for c-Fos and transmitter markers. Rats were administered three doses of caffeine or saline vehicle during the light phase. Caffeine at 10 and 30 mg/kg, i.p., increased motor activities, including locomotion, compared with after saline or a higher dose, 75 mg/kg. The three doses of caffeine induced distinct dose-related patterns of c-Fos immunoreactivity in several arousal-promoting areas, including orexin neurons and adjacent neurons containing neither orexin nor melanin-concentrating hormone; tuberomammillary histaminergic neurons; locus coeruleus noradrenergic neurons; noncholinergic basal forebrain neurons that do not contain parvalbumin; and nondopaminergic neurons in the ventral tegmental area. At any dose used, caffeine induced little or no c-Fos expression in cholinergic neurons of the basal forebrain and mesopontine tegmentum; dopaminergic neurons of the ventral tegmental area, central gray, and substantia nigra pars compacta; and serotonergic neurons in the dorsal raphe nucleus. Saline controls exhibited only few c-Fos-positive cells in most of the cell groups examined. These results indicate that motor-stimulatory doses of caffeine induce a remarkably restricted pattern of c-Fos expression in the arousal-promoting system and suggest that this specific neuronal activation may be involved in the behavioral arousal by caffeine.

Animals↗
PubMed1982

Induction of sister chromatic exchanges and inhibition of cellular proliferation in vitro. I. Caffeine.

Cytogenetic assay systems based on the detection of sister chromatid exchanges (SCE) are widely advocated as a sensitive screening method for assessing genotoxic potential. While many agents have been examined for their ability to induce SCE's, complete dose-response information has often been lacking. We have reexamined the ability of one such compound-caffeine-to induce SCEs and also to inhibit cellular proliferation in human peripheral lymphocytes in vitro. An acute exposure to caffeine prior to the DNA synthetic period did not affect either SCE frequency or the rate of cellular proliferation. Chronic exposure to caffeine throughout the culture period lead to both a dose-dependent increase in SCEs (SCEd or doubling dose = 2.4 mM; SCE10 or the dose capable of inducing 10 SCE = 1.4 mM) and a dose-dependent inhibition of cellular proliferation (IC50 or the 50% inhibition concentration = 2.6 mM). The relative proportion of first generation metaphase cels, an assessment of proliferative inhibition, increased linearly with increasing caffeine concentrations. However, SCE frequency increased nonlinearly over the same range of caffeine concentrations. Examination of the ratio of nonsymmetrical to symmetrical SCEs in third generation metaphase cells indicated that caffeine induced SCEs in equal frequency in each of three successive generations. The dependency of SCE induction and cellular proliferative inhibition on caffeine's presence during the DNa synthetic period suggests that caffeine may act as an antimetabolite in normal human cells. The significance of these results in regard to both caffeine's genotoxic potential and to the reliability of the SCE assay system are discussed.

Caffeine↗
PubMedDate not supplied

The excretion of caffeine in the semen of men: pharmacokinetics and comparison of the concentrations in blood and semen.

The concentration of caffeine in the blood and semen of men was measured after an oral dose of 200 or 400 mg caffeine. Caffeine was rapidly absorbed (mean tmax = 0.76 +/- 0.12 hour), with an average maximum concentration in the blood of 7.4 micrograms/ml for the 400-mg dose and 3.4 micrograms/ml for the 200-mg dose. The mean clearance of caffeine was 161 and 156 ml/min, while the mean volume of distribution was 50 and 47 liters for the 400- and 200-mg doses, respectively. Distribution of caffeine into the semen was rapid, with a concentration of caffeine in the semen almost identical to that observed concurrently in the blood (blood/semen concentration ratio = 0.97). The mean half-life of caffeine in the blood and semen was 3.7 and 3.6 hours, respectively, indicating that the decline of caffeine in the blood is very similar to that in semen. Thus, caffeine partitions rapidly into and out of the prostatic and seminal vesicular secretions, which contribute to the formation of the ejaculate.

Adult↗