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PubMed1988

Characterization of the enhancing effect of caffeine on sister-chromatid exchanges induced by ultraviolet radiation in excision-proficient xeroderma pigmentosum lymphoblastoid cells.

Cells of some excision-proficient xeroderma pigmentosum (XP) cell lines are highly sensitive to post-UV caffeine treatment in terms of sister-chromatid exchange (SCE) induction as well as cell lethality. In the present study, we conducted a detailed investigation of the enhancing effect of caffeine on SCE frequency induced by UV in excision-proficient XP cells, and obtained the following results. (1) Continuous post-UV treatment with 1 mM caffeine markedly enhances UV-induced SCEs and such enhanced SCEs occur with similar frequency during either the 1st or the 2nd cell cycle in the presence of caffeine and 5-bromodeoxyuridine (BrdUrd). (2) The high sensitivity of the cells to post-UV caffeine treatment persists for at least 2 days after UV when irradiated cells are held in either the proliferating or the nonproliferating state prior to the addition of BrdUrd. (3) Caffeine exerts its effect on cells in S phase. (4) Neither BrdUrd in the medium nor the incorporated 5-bromodeoxyuridine monophosphate (BrdUMP) in DNA plays an appreciable role in the expression of the enhancing effect of caffeine. The most likely explanation for our findings is as follows. In excision-proficient XP cells, the cause of SCE formation such as UV-induced lesions or resulting perturbations of DNA replication persists until the 2nd round or more of post-UV DNA replication. If caffeine is given as post-UV treatment, such abnormalities may be amplified, resulting in a synergistic increase in SCE frequency.

Adult↗
PubMed1988

Effects of caffeine on mood and memory.

The effects of caffeine on mood and memory tasks were investigated in a double-blind study of 95 healthy young adults who were randomly assigned to three doses: 0, 200, and 400 mg of oral administration of caffeine. Subjects completed a battery of tasks once predrug and several times postdrug. Caffeine, in general, showed nonsignificant effects on cognitive, learning, and memory performance. The exception is that 200 mg caffeine facilitated performance on the relatively more difficult cancellation (addition and multiplication) tasks than the digit cancellation task. In addition caffeine decreased boredom and relaxation, and increased other ratings of subjective moods--anxiousness, tenseness, and nervousness. The reduction in boredom or fatigue is associated with the repetitive nature of the task and the period of time during which the tasks were repeated. In general, high-to-moderate users of caffeine recalled more words than low users, particularly at the beginning of the lists. Results are discussed in terms of the effects of caffeine on task difficulty and sensitivity and the relative potency of caffeine doses on behavior. User effect is suggested as an important consideration of memory assessment.

Adult↗
PubMed1991

Lasting effects of early chronic caffeine feeding on rats' behavior and brain in later life.

Pregnant dams were fed a 20% protein diet with caffeine (2 mg/100 g b.wt.), starting on day 9 of gestation. At birth, each dam with 8 assigned pups was fed this diet until weaning, day 22. On day 22, female rats were caged and fed this diet until day 93. Starting on day 93, the caffeine-supplemented diet was replaced with a caffeine-free, 20% protein diet until day 388. Starting on day 31, each animal was placed in a photoactivity cage, and locomotive activity was measured until day 375. On day 388, the animals were killed, and their brains were removed and divided into 7 regions. The weight, DNA, protein and zinc contents, and alkaline phosphatase activity of each region were determined. Locomotive activity of the caffeine-fed group was higher than in the noncaffeine control group. Accumulative activity scores showed 3 subgroups (high, medium, and low) in both groups at day 93. The medium activity subgroup in the caffeine group was greater than the controls from day 72 to day 93. These differences reappeared 5 weeks after cessation of caffeine supplementation and continued until day 375. The differences in activity were minimum in the high and low subgroups. Chronic caffeine intake in early life permanently affected the medium activity subgroup. Furthermore, various regions of the brain were biochemically altered in spite of the feeding of a noncaffeine diet for almost 300 days after caffeine.

Animals↗
PubMed1993

Effects of caffeine and gender on physiology and performance: further tests of a biobehavioral model.

The present study extended testing of our biobehavioral model describing the effects of arousal and caffeine to include an examination of gender differences and their interactions with habitual and acute caffeine ingestion. Males and females selected as high or low habitual caffeine users were randomly assigned to receive either caffeine or a placebo and exposed to novel and repetitive recall tasks and to simple auditory stimuli. Electrodermal activity and recall task performance were recorded. The four major factors examined, including habitual caffeine use, acute ingestion, gender, and stimulus novelty, affected behavior, physiology, or both. Results showed that habitual caffeine usage systematically affected tonic arousal (skin conductance level) and improved recall task performance. Acute caffeine ingestion increased phasic arousal (skin conductance response amplitude) and reduced habituation rates. Gender interacted with other factors to significantly affect both tonic and phasic arousal, and females performed better than males on the recall tasks. These results were partially supportive of the theoretical model, and further work is needed to examine the interactions of acute and chronic caffeine intake with gender and novelty.

Adult↗
PubMed1985

Effect of nicotine and caffeine pretreatment on the gastric mucosal damage induced by aspirin, phenylbutazone, and reserpine in rats.

The effect of nicotine and caffeine pretreatment by feeding nicotine (2.5 mg %), caffeine (30 mg % base), and their combination (nicotine 2.5 mg % + caffeine 30 mg %) in drinking water ad libitum for 21 days was studied on the gastric mucosal damage induced by aspirin, phenylbutazone, and reserpine in rats. When given alone, neither nicotine nor caffeine produced any visibly discernible gastric lesions. Their concurrent administration too, did not produce any gastric mucosal injury. Pretreatment with nicotine, caffeine, and their combination resulted in significant augmentation of gastric ulcers produced by aspirin, phenylbutazone, and reserpine. However, caffeine administration produced a comparatively less profound augmentation of experimentally induced gastric lesions than that produced by nicotine pretreatment. The enhancement of gastric ulcers in the groups pretreated with the combination of nicotine and caffeine followed by one of the drugs was significantly greater than in the groups treated by either of them alone. The effect of nicotine on the mucus neck cell population of the gastric mucosa and on pancreatic bicarbonate secretion and the gastric secretory effect of caffeine may be responsible for the potentiation of the ulcerogenic effects of aspirin, phenylbutazone, and reserpine.

Administration, Oral↗
PubMedDate not supplied

Caffeine and its effects on pregnancy and the neonate.

In animal studies, fetal loss, decreased fetal weight and size, and major skeletal defects have been reported when dosages of more than 80 mg/kg of caffeine were used. Human epidemiologic studies that examine the relationship between caffeine use and congenital abnormalities are not conclusive; however, there is some evidence to suggest a caffeine effect upon fetal growth patterns. Because caffeine drinking is so often associated with the use of other drugs such as tobacco, it is difficult to ascertain which drug has the effect on growth, or if it is a combined effect from both drugs. A tripling of the half-life of caffeine in the last two trimesters of pregnancy resulting in much higher caffeine blood levels for both mother and fetus, combined with the neonate's inability to metabolize caffeine, could account for the indications of neonatal caffeine withdrawal observed in the first week after birth.

Abnormalities, Drug-Induced↗
PubMed1982

Caffeine-induced hypodipsia in water-deprived rats: relationships with benzodiazepine mechanisms.

The effects of caffeine (3-100 mg/kg) on water intake and the time course of drinking were investigated in male rats which had been adapted to a daily 22 hr water deprivation schedule. Doses of caffeine were found which significantly depressed water intake, reduced the time to the first interruption in drinking, and depressed the time course of drinking, without manifestly affecting the efficiency of drinking. At the highest dose, however, caffeine had a major suppressant effect on drinking, which was accompanied by signs of motor interference. The hypodipsic effect of caffeine was reversed by benzodiazepine treatment (midazolam or diazepam). However, the convulsant benzodiazepine Ro5-3663 which on electrophysiological evidence can act as a GABA antagonist also reduced drinking, adding to the hypodipsic effect of caffeine. A water load prior to the drinking test produced satiation effects, closely reminiscent of the effects of caffeine at lower doses. The possible mimicry of thirst satiety by caffeine is discussed, together with possible underlying mechanisms of caffeine-benzodiazepine interactions.

Animals↗
PubMed1987

Different genes specify hyporesponsiveness to seizures induced by caffeine and the benzodiazepine inverse agonist, DMCM.

Two strains of inbred mice differed significantly in their susceptibility to tonic seizures induced by caffeine and the benzodiazepine inverse agonist, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The hyporesponsive strain, SWR, was not less susceptible to the convulsant action of other chemical convulsants, an observation which indicated that the response differences between the strains were pharmacologically specific. These observations and drug interaction studies suggested that caffeine-induced seizures might be mediated through an "inverse" agonist-like action of caffeine on benzodiazepine receptors associated with GABA receptor-benzodiazepine receptor-chloride ionophore complex. To determine whether the coincident alteration in susceptibility to DMCM and caffeine resulted from a single mutational change or was the result of two different genetic changes occurring coincidentally between these two strains of mice, progeny from conventional Mendelian crosses (F1, F2 and reciprocal backcrosses) were analyzed for the co-segregation of susceptibility to DMCM and caffeine. The inheritance of DMCM sensitivity was consistent with a single autosomal gene determinant in which the allele specifying increased responsiveness was dominant to the allele determining hyporesponsiveness. The frequent occurrence of recombinant phenotypes (e.g., caffeine hyporesponsive but DMCM sensitive mice) among F2 and backcross progeny established that different genetic determinants encode DMCM susceptibility and caffeine susceptibility in these two strains of mice. Thus, while these data establish a simply inherited difference in benzodiazepine responsiveness between the two mouse strains, they also indicate that this pair of strains is inappropriate for a genetic analysis aimed at probing the relationship between caffeine-induced seizures and the benzodiazepine receptor.

Animals↗
PubMed1988

Tolerance to behavioral effects of caffeine in rats.

Tolerance develops to three behavioral effects of caffeine in rats treated daily with the drug: stimulation of locomotor activity, rate-decreasing effect on food-reinforced operant responding, and discriminative stimulus effects. Tolerance induced by caffeine to stimulation of locomotor activity: (1) develops rapidly, being nearly maximal 24 hr after the start of daily treatment with 35-40 mg/kg in four divided oral doses; (2) is insurmountable (i.e., complete) so that rats are unresponsive, even to high doses of caffeine, and dose-response curves are displaced downward and flattened; (3) is pharmacologically specific, extending to other methylxanthines but not to nonxanthine psychomotor stimulants. Tolerance to the other two behavioral effects of caffeine: (1) appears to develop gradually; (2) is surmountable so that dose-response curves are displaced to the right; (3) extends to nonxanthine psychomotor stimulants, methylphenidate, in the case of discriminative effects. Thus, at least two distinct types of tolerance to behavioral effects of caffeine in the rat can be identified. The potency of an adenosine analog, R(-)-PIA, in depressing locomotor activity does not increase during or 24 hr after termination of chronic daily treatment with caffeine when rats are completely tolerant to caffeine-induced stimulation of locomotor activity. These results do not support the view that enhanced functional sensitivity of central adenosine systems (e.g., up-regulation of receptors) is the mechanism of tolerance to the stimulant effect of caffeine on locomotor activity.

Animals↗
PubMed1989

Behavioral interaction between cocaine and caffeine: a drug discrimination analysis in rats.

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine greater than cocaine greater than caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeine's effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as "supra-additive," in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.

Animals↗
PubMed1989

Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors.

The purpose of this study was to determine the mechanism by which caffeine increases anxiety. Rats were tested in the social interaction test of anxiety after administration of caffeine (20 or 40 mg/kg) alone or in combination with various compounds. In order to investigate the role of adenosine receptors, caffeine was given in combination with 2-chloroadenosine (0.1 and 1 mg/kg). To investigate the role of benzodiazepine receptors, chlordiazepoxide (5 mg/kg), a benzodiazepine antagonist, flumazenil (RO 15-1788, 1 and 10 mg/kg) and a triazolobenzodiazepine U-43,465 (32 mg/kg) were used. Finally, an alpha 2-receptor agonist, clonidine (0.1 and 0.025 mg/kg) and a beta-adrenoceptor antagonist, DL-propranolol (5 mg/kg), were used to study the role of noradrenergic systems in the effects of caffeine. Caffeine (20 and 40 mg/kg) reduced the time spent in social interaction and this effect was antagonized by chlordiazepoxide, U-43,465 and DL-propranolol, but not by flumazenil, 2-chloroadenosine or clonidine. It was therefore concluded that the anxiogenic effect of caffeine was unlikely to be due to its effects at adenosine or benzodiazepine receptors. It is suggested that the reversal of caffeine's effects by chordiazepoxide may have been "functional," i.e., merely a cancellation of two opposite effects. It is discussed whether the reversal of caffeine's effects by propranolol and U-43,465 are functional, or reflect a noradrenergic site of action.

2-Chloroadenosine↗
PubMed1990

Effects of uric acid and caffeine on A1 adenosine receptor binding in developing rat brain.

Previous studies have demonstrated that elevated levels of serum uric acid or caffeine are associated with increased locomotor activity in rats and humans. Since uric acid and caffeine are structurally similar, it was hypothesized that these compounds alter locomotor activity through a common neural mechanism, specifically by acting as receptor antagonists at adenosine A1 binding sites. In vitro competition of caffeine and uric acid against the A1 agonist, [3H] cyclohexyladenosine ([3H]CHA), was conducted using homogenates of adult rat forebrain. Caffeine effectively competed for the A1 binding site as previously reported (IC50 = 107 microM), but uric acid failed to compete with [3H]CHA binding at concentrations within a relevant physiological range. Nevertheless, in vivo experiments indicated that chronic elevation of uric acid following allantoxanamide treatment of male rats on days 4-27 of life significantly decreased A1 receptor binding in the striatum, a region traditionally implicated in mammalian locomotion. In contrast, chronic caffeine treatment on days 4-27 of life caused an increase in A1 receptor binding in the cortex similar to increases reported previously in whole brain. These changes in A1 receptor binding following chronic elevation of uric acid or caffeine did not persist in rats that had been withdrawn from allantoxanamide or caffeine treatment for 14 days. Results from in vitro and in vivo experiments indicate that despite a similar molecular structure uric acid does not act by the same mechanism as caffeine to increase locomotor activity in rats.

Adenosine↗
PubMed1995

Dose-dependent surmountability of locomotor activity in caffeine tolerance.

For two chronic intraperitoneal caffeine dose regimens (10 and 80 mg/kg per day), tolerance developed rapidly (2-3 days) to the stimulatory effects of caffeine on locomotor activity. However, surmountability of the tolerant activity rate levels by caffeine administration was dose dependent: Activity rate was restored fully by acute caffeine administration for the 10 mg/kg per day series, but not for the 80 mg/kg per day series. The extent of tolerance was also dose-dependent: Tolerance was incomplete for the low-dose daily caffeine series but complete for the high-dose series. Upon discontinuation of daily caffeine dosing, activity rate decreased to the original baseline levels for both chronic series. Caffeine tolerance and the quantification of its surmountability may be explained by the pharmacokinetics of caffeine and the upregulation of adenosine receptors.

Animals↗
PubMed1995

The effects of different doses of caffeine on habituation of the human acoustic startle reflex.

Research in this laboratory showed that caffeine (4 mg/kg) delays habituation of the acoustic startle reflex in humans. The present study examined the effects of 2- and 6-mg/kg doses of caffeine on acoustic startle habituation in moderate-high and low caffeine users. Eyeblink responses to 30 trials of 85-dB noise stimuli were measured beginning 30 min after oral ingestion of either placebo or 2 or 6 mg/kg of caffeine. The 2-mg/kg dose of caffeine delayed startle habituation in both moderate-high and low caffeine users. The 6-mg/kg dose produced no differential effects on startle responding from placebo. In moderate-high users, following habituation, startle responding was smaller in the placebo condition compared to both caffeine conditions. In low users there were no differences in posthabituation responding between doses, suggesting that this dose effect is dependent on a history of chronic caffeine usage.

Acoustic Stimulation↗
PubMed1993

Accumulation of theophylline, theobromine and paraxanthine in the fetal rat brain following a single oral dose of caffeine.

This paper describes the disposition of caffeine and its metabolites, theophylline, theobromine and paraxanthine in the 20-day fetal and adult brains following a single maternal dose of 5 or 25 mg/kg caffeine. Brains and plasma were collected 5 and 30 min, and 1, 3, 8 and 24 h after dosing. It was found that fetal and adult caffeine AUC (area under the concentration-time curve) values did not differ between the brain and plasma at either dose. Caffeine's primary metabolites theophylline, theobromine and paraxanthine did, however, accumulate in the fetal brain at both doses resulting in a 3-fold increase in brain metabolite exposure compared to fetal circulatory levels. In contrast to the fetus, metabolite AUC values after a dose of 25 mg/kg were found to be lower in the brains of adults compared with plasma. This suggests that caffeine's primary metabolites might be selectively excluded from the adult brain. In conclusion we have shown that, unlike the adult, the fetal rat brain accumulates theophylline, theobromine and paraxanthine when exposed to caffeine doses comparable to those attainable by normal human consumption. Since many aspects of caffeine metabolism are similar in the rat and human, we suggested that particular attention should be paid to the consumption of caffeine during pregnancy.

Animals↗
PubMed1995

Neonatal caffeine exposure alters seizure susceptibility in rats in an age-related manner.

Early developmental exposure to caffeine in rats results in decreased susceptibility to certain chemically-induced seizures in the adult. To determine whether this effect first appears in adulthood or is present during preceding developmental stages, we exposed neonatal rats to caffeine and determined seizure thresholds in animals 28, 42 and 70-90 days of age. Rats were unhandled or received either vehicle (water) or caffeine (15-20 mg/kg/day) by gavage (0.05 ml/10 g) over postnatal days 2-6. At 28, 42, or 70-90 days of age, rats were infused intravenously with picrotoxin (PIC), bicuculline (BIC), pentylenetetrazol (PTZ), caffeine (CAFF), strychnine (STR), or kainic acid (KA). Seizure thresholds for each compound were analyzed as a function of neonatal treatment, sex, and age. At 28 days, neonatally caffeine-exposed rats had a higher seizure threshold only for PTZ (P < 0.03). At 42 days, neonatally caffeine-exposed rats had higher seizure thresholds for PIC (P < 0.0007) and PTZ (P < 0.0001) than did controls. These results at 28 and 42 days are compared with previously reported data that demonstrated that in adulthood, rats neonatally exposed to caffeine have higher thresholds for seizure induction with CAFF, PTZ, and KA. Thus, early developmental exposure to caffeine results in decreases in seizure susceptibility that are agent specific and may result in a delay in the decrease in seizure threshold that occurs for many agents between late juvenile ages and adulthood.

Aging↗
PubMed1987

Abrogation of the effects of aphidicolin on NIH3T3 and V79 cells by caffeine.

In this communication I show that caffeine (1,3,7-trimethylxanthine) stimulates [3H]thymidine incorporation in aphidicolin-treated V79 and NIH3T3 cells. Flow microfluorometric analysis showed that caffeine, partially or fully, abrogates the cell cycle progression block produced by aphidicolin. Increased cell growth is also observed in cultures treated with both aphidicolin and caffeine compared to cultures treated with aphidicolin only. Microscopic examination of V79 cultures treated with aphidicolin for 8 h showed a marked reduction in the frequency of round mitotic cells, as is expected from a drug which inhibits progression through the cell cycle by inhibiting DNA replication; this effect of aphidicolin was also reduced by caffeine. Biochemical analysis showed that caffeine did not directly interfere with the inhibition of DNA polymerase-alpha by aphidicolin. Analysis of dNTP pools indicated that caffeine increased the level of dCTP in V79 cells. In aphidicolin-treated V79 cells, the increase in the dCTP level due to exogenous cytidine was almost completely blocked; caffeine also substantially overcame this effect of aphidicolin. These results indicate that caffeine produces its effects on aphidicolin-treated cells by altering the dCTP metabolism.

Animals↗
PubMed1984

Comparative analysis of caffeine and 3-aminobenzamide as DNA repair inhibitors in Syrian baby hamster kidney cells.

The effects of caffeine and 3-aminobenzamide (3-AB) on Syrian baby hamster kidney cells treated with DNA-alkylating agents and ultraviolet-light suggest that two different DNA-repair mechanisms are involved. Both these agents enhanced the cell kill after methyl methanesulfonate (MMS) treatment. However, enhanced lethality was observed only with caffeine post-treatment when cells were exposed to nitrogen mustard (HN2) or ultraviolet light (UV); 3-AB did not appreciably change cell killing by these agents. With MMS-treated cultures, the effect of caffeine was maximal about 16 h later. The effect of 3-AB on the other hand, was exerted during the first 4 h after exposure to MMS. Caffeine's effect on cell survival could be abolished by low concentrations of cycloheximide, whereas 3-AB's effect could not. Furthermore, the G2 block in cell cycle progression, after MMS treatment, was not observed if the cells were post-treated with caffeine. In the presence of 3-AB, MMS-treated cells were arrested in G2 phase at a much earlier time compared to cells not treated with 3-AB. Finally caffeine post-treatment produced a 10-fold increase in nuclear fragmentation in MMS-treated cells. 3-AB did not cause nuclear fragmentation by itself but further enhanced the nuclear fragmenting effect of caffeine when both agents were present during the posttreatment. Therefore, we propose that 3-AB and caffeine each prevent a different repair mechanism from being effective.

Animals↗