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PubMed2000

The pharmacokinetics of caffeine in Nigerian children suffering from malaria and kwashiorkor.

OBJECTIVES: Caffeine-containing beverages are generally consumed by Nigerians suffering from malaria and kwashiorkor in the belief that caffeine aids early recovery from these illnesses, which are common in the tropics. However, there are no studies on the influence of these diseases on the absorption and pharmacokinetics of caffeine in Africans. MATERIALS AND METHODS: A single oral dose of caffeine was given to five healthy children and to five and seven children suffering from malaria and kwashiorkor, respectively. Caffeine and its dimethylxanthine metabolites were measured in plasma using high-performance liquid chromatography. RESULTS: The maximum plasma concentration (Cmax) of caffeine and the time of Cmax were similar (P > 0.05) in the three groups. However, the elimination half-life of caffeine was significantly longer in children with malaria (9.2 +/- 3.5 h) (P < 0.01) and kwashiorkor (13.1 +/- 7.9 h) (P < 0.05) than in the healthy controls (3.7 +/- 1.8 h). The total plasma oral clearance of caffeine of 4.4 +/- 1.9 ml/min/kg in healthy children was significantly higher (P < 0.01) than in those with kwashiorkor (2.0 +/- 0.9 ml/min/kg) and malaria (1.6 +/- 1.0 ml/min/ kg) (P < 0.05). Paraxanthine was the principal metabolite in all the three groups with Cmax significantly higher in healthy children (1.3 +/- 0.3 microg/ml) than in children with malaria (0.8 +/- 0.4 microg/ml) (P < 0.05) and kwashiorkor (0.3 +/- 0.1 microg/ml) (P < 0.0001). CYP1A2 activity, measured by the plasma ratios of paraxanthine: caffeine, was significantly lower in kwashiorkor and malaria. CONCLUSIONS: This study showed that the plasma kinetics of caffeine are significantly altered in malaria and kwashiorkor, and CYP1A2 activity was lower in these two disease groups.

Administration, Oral↗
PubMed1998

Measurement of SR Ca2+ content in the presence of caffeine in permeabilised rat cardiac trabeculae.

This study was designed to measure the Ca2+ content of rat cardiac sarcoplasmic reticulum (SR) after equilibration with normal diastolic levels of Ca2+ (100 nM), in the absence and presence of caffeine. Measurements of [Ca2+] based on Fura-2 fluorescence were made from a limited bath volume (230 nl) containing individual saponin-permeabilised rat cardiac trabeculae. Injection of caffeine (5-40 mM) into this volume caused an initial release of Ca2+ from the SR, but within 30 s the SR was able to re-accumulate a significant proportion of the Ca2+. Ca2+ re-accumulation into the SR could be prevented by removal of ATP to inhibit the SR Ca2+ pump. Incubation of the preparation in an ATP-containing solution containing caffeine (5-40 mM) and 100 nM Ca2+ indicated that the SR's ability to retain Ca2+ depends inversely on the dose of caffeine. The relative Ca2+ content of the SR after preincubation with caffeine was 86.7+/-3.5% at a caffeine concentration of 5 mM, 62.5+/-5.1% at 10 mM caffeine, 37.8+/-8.1% at 20 mM caffeine and 7. 1+/-1.9% at 40 mM caffeine. Measurement of the SR Ca2+ release in the presence of different BAPTA concentrations was used to calculate (1) the Ca2+-binding capacity of the preparation (equivalent to 245+/-10 microM BAPTA) and (2) the Ca2+ content of the SR accessed by caffeine after equilibration with 100 nM Ca2+ (186+/-11 micromol/l cell volume or 5.6 mmol/l SR volume).

Adenosine Triphosphate↗
PubMed2006

Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats.

Caffeine, the most widely consumed psychostimulant drug, acutely stimulates motor behaviour and enhances dopamine agonists actions whilst chronically it induces tolerance to either caffeine- or dopamine agonist-induced motor activating effects. The present study examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity. To this end, motor activation and rotational behaviour stimulated by either caffeine or D-amphetamine (0.5, 2 mg/kg), given 3 days after the last caffeine administration, were evaluated in neurologically intact and unilaterally 6-hydroxydopamine-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor and turning behaviour. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-hydroxydopamine-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects, rather than in tolerance, and induces neuroadaptive facilitatory changes in dopamine transmission.

Adrenergic Agents↗
PubMed2006

Catabolic pathways and biotechnological applications of microbial caffeine degradation.

Catabolism of caffeine (1,3,7-trimethylxanthine) in microorganisms commences via two possible mechanisms: demethylation and oxidation. Through the demethylation route, the major metabolite formed in fungi is theophylline (1,3-dimethylxanthine), whereas theobromine (3,7-dimethylxanthine) is the major metabolite in bacteria. In certain bacterial species, caffeine has also been oxidized directly to trimethyl uric acid in a single step. The conversion of caffeine to its metabolites is primarily brought about by N-demethylases (such as caffeine demethylase, theobromine demethylase and heteroxanthinedemethylase), caffeine oxidase and xanthine oxidase that are produced by several caffeine-degrading bacterial species such as Pseudomonas putida and species within the genera Alcaligenes, Rhodococcus and Klebsiella. Development of biodecaffeination techniques using these enzymes or using whole cells offers an attractive alternative to the present existing chemical and physical methods removal of caffeine, which are costly, toxic and non-specific to caffeine. This review mainly focuses on the biochemistry of microbial caffeine degradation, presenting recent advances and the potential biotechnological application of caffeine-degrading enzymes.

Bacterial Proteins↗
PubMed1988

Effect of behavior state on caffeine's ability to alter blood pressure.

Caffeine use during exposure to mental stress is an extremely common occurrence. Because both have been shown to alter blood pressure (BP) and its underlying hemodynamic mechanisms, the potential exists for additive or even synergistic effects. Changes in heart rate, BP and noninvasive thoracic impedance measures of left ventricular function were examined in young men (ages 20 to 36) at rest and during a demanding behavioral task performed 40 minutes after predosing with caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of coffee) or placebo in a double-blind crossover design. All subjects were healthy young men without history of cardiovascular disease, regular use of nicotine, recreational or prescription drugs or caffeine intolerance. Caffeine abstinence was required for 12 hours before each test session. Systolic and diastolic BP were elevated by both caffeine and the behavioral task alone (p less than 0.01 for each); when combined, caffeine's pressor effects were additive to those of the behavioral task. However, caffeine's pressor effect was produced by different mechanisms depending on the behavioral state. Caffeine increased systemic vascular resistance (p less than 0.01) under resting conditions, but it enhanced cardiac output (p less than 0.01) during behavioral arousal associated with the task. The combined influence of caffeine and the task increased the number of men in whom peak systolic BP reached hypertensive levels, and also synergistically increased cardiac minute work (p less than 0.01) and the rate-pressure product estimate of myocardial oxygen demand (p less than 0.05). Implications of these findings are discussed for long standing theoretical disputes regarding caffeine, its health consequences, and for methodologic issues in behavioral and clinical studies.

Adult↗
PubMed1990

Effects of caffeine on blood pressure response during exercise in normotensive healthy young men.

The possible combined effects of caffeine and exercise on blood pressure (BP) regulation were examined in 34 healthy, normotensive (BP less than 135/85 mm Hg) young men (mean age 27 +/- 3 years) in a placebo-controlled, double-blind crossover design. Each subject performed submaximal and symptom-limited maximal supine bicycle exercise 1 hour apart after ingestion of placebo or caffeine (3.3 mg/kg). Heart rate, BP, cardiac output and peripheral vascular resistance were compared for placebo and caffeine days. Postdrug baseline showed that caffeine increased systolic and diastolic BP and peripheral vascular resistance (p less than 0.001 for each) and decreased heart rate (p less than 0.01) but did not change stroke volume or cardiac output. BP and vascular resistance effects of caffeine remained during submaximal exercise resulting in an additive increase in BP while negative chronotropic effects of caffeine disappeared. At maximal exercise substantially more subjects (15 on caffeine vs 7 on placebo, p less than 0.02) had systolic BP greater than or equal to 230 mm Hg and/or greater than or equal to 100 mm Hg for diastolic BP. Plasma norepinephrine levels were not significantly different across days, but epinephrine was higher at maximal exercise and cortisol was increased post-drug and throughout maximal exercise on caffeine days. Data indicate that caffeine increases BP additively during submaximal exercise and may cause excessive BP responses at maximal exercise for some individuals. The pressor effects of caffeine appear to be due to increasing vascular resistance rather than cardiac output.

Adult↗
PubMed1983

Caffeine-induced potentiation of GABA effects on frog spinal cord: an electrophysiological study.

A parasagittal slice of the frog spinal cord was kept in vitro for electrophysiological recordings from dorsal and ventral roots. Low concentrations of caffeine (50 microM) which had relatively small effects on baseline electrical activity, increased the depolarizing action of GABA on dorsal root fibres by 50%. A similar result was also obtained when GABA motoneuronal responses were tested. On dorsal roots the potentiation of GABA responses by caffeine was reflected by a significant decrease in GABA ED50 value without change in the maximal response amplitude; this enhancing action of caffeine was not blocked by bicuculline (5 microM) but was abolished by flurazepam (5 microM) or by Ca2+ antagonists (Mn2+ and Cd2+). Blockade of interneuronal activity by procaine left the potentiating action of caffeine unchanged. High doses of caffeine (up to 1 mM) produced a seemingly non-competitive antagonism of GABA responses. We suggest that caffeine can modulate GABA responses through two different mechanisms: a potentiation of GABA effects (seen with low doses of caffeine) probably due to Ca2+ mobilization and an antagonism of GABA responses (typically seen with large doses of caffeine) perhaps caused by block of GABA receptor-activated channels. This novel caffeine-GABA interaction may be useful to interpret some of the effects of caffeine on mammalian behaviour.

Animals↗
PubMed1987

Discriminative stimulus effects of caffeine: tolerance and cross-tolerance with methylphenidate.

Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days shifted the caffeine stimulus generalization curve to the right by 3-fold in rats trained to discriminate saline from 30 mg/kg of caffeine, and by 4-fold in rats trained to discriminate saline from 10 mg/kg of caffeine. The latter group was also tested for cross-tolerance with methylphenidate, a drug that generalizes completely with caffeine. Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days increased the ED50 of methylphenidate for caffeine-appropriate responding from 1.5 to 5.5 mg/kg. Conversely, injections of methylphenidate (3.0 mg/kg) increased the ED50 of caffeine from 5.2 to 15 mg/kg. The development of symmetrical cross-tolerance to the discriminative effects of caffeine and to the caffeine-like discriminative effects of methylphenidate supports previous observations suggesting commonalities in the cellular bases of the stimulus properties of these drugs.

Animals↗
PubMed1995

Pharmacological natures of caffeine-induced endothelium-dependent and -independent contraction in canine mesenteric artery.

The present experiments were carried out to elucidate whether pharmacological nature of caffeine (1 mM)-induced endothelium-dependent contraction (EDC) is different from that of caffeine (10 mM)-induced endothelium-independent contraction (EIC) in canine mesenteric artery. Caffeine (1 mM)-induced EDC was abolished when arterial strips were incubated in Ca(++)-free medium for 20 min, but EIC was not abolished. EGTA and EDTA (0.5 and 1 mM) attenuated the EDC, and at the concentration of 2.5 mM completely abolished the EDC. Nifedipine (10(-6) and 3 x 10(-6) M), diltiazem (10(-6) M) and verapamil (10(-6) M) did not affect the caffeine (1 mM)-induced EDC. Lemakalim (10(-8), 3 x 10(-8) and 10(-7) M) attenuated the caffeine (1 mM)-induced EDC in a concentration-dependent manner. Lemakalim (10(-7) M) nearly abolished the EDC. The inhibitory effect of lemakalim (10(-7) M) on the EDC was antagonized in the presence of glibenclamide (3 x 10(-6) M). In contrast, caffeine (10 mM)-induced EIC was resistant to lemakalim at higher concentration (3 x 10(-7) M). Forskolin (10(-7), 3 x 10(-7) and 10(-6) M) significantly attenuated both the caffeine (1 mM)-induced EDC and caffeine (10 mM)-induced EIC. The inhibitory effect of forskolin on the EDC was augmented in the presence of rolipram (10(-6) M). Nitroglycerin (10(-5) M) attenuated significantly caffeine-induced both EDC and EIC. The inhibitory effect of nitroglycerin on the EDC was augmented in the presence of zaprinast (10(-5) M). The present experiments demonstrate that caffeine-induced EDC is due to nifedipine-resistant and lemakalim-sensitive Ca++ mobilization and the EIC is due to both nifedipine- and lemakalim-resistant Ca++ mobilization in canine mesenteric artery.

Adenylyl Cyclases↗
PubMed1981

Complex interactions of caffeine and its structural analogs with ultraviolet light in cell killing.

We measured the clonogenic survival response of cultured mouse 10T1/2 cells exposed to UV light and caffeine post-treatment. When 0.5 and 1 mM caffeine were present for 24 h immediately following UV, the D0 values of the biphasic survival curves suggest that one subpopulation was sensitized and one subpopulation was protected from killing by UV light. A cloned survivor from the radioprotected subpopulation responded to UV plus caffeine in identical manner as the parent cells. When the caffeine exposure was prolonged to 48 h, only the radiosensitizing effect was observed. Two demethylated analogs of caffeine were also tested. The response of 10T1/2 cells to 1 mM theophylline present for 24 h after UV irradiation was approximately the same as that for the same treatment with 1 mM caffeine. However, prolonging the theophylline exposure to 48 h failed to produce the same kind of potentiation of cell killing as that observed for caffeine. Xanthine by itself was as toxic to 10T1/2 cells as caffeine, but had no synergistic effect as caffeine when given to UV-irradiated cells for 24 or 48 h. It is therefore unlikely that all the effects of caffeine on UV-irradiated cells are mediated by its demethylated metabolites.

Animals↗
PubMed1987

Caffeine enhancement of saccharin but not cyclamate flavor avoidance.

The present experiments were designed to assess whether caffeine, a substance that potentiates human perception of some artificial sweeteners, might also enhance perception of such substances by rats. In Experiment 1, rats were given varied concentrations of saccharin, cyclamate, and caffeine in 2-choice tests. 'Indifference thresholds' for these substances were 3.9 X 10(-4) M, 1 X 10(-3) M, and 1.6 X 10(-7) M, respectively. In Experiment 2, concentrations of saccharin and cyclamate just above and below indifference were used as stimuli in a flavor avoidance learning (FAL) paradigm. 'Suprathreshold' concentrations of saccharin and cyclamate produced reliable FAL while 'subthreshold' concentrations did not. In Experiment 3, rats were exposed to a low concentration of caffeine followed by presentations of subthreshold concentrations of saccharin or cyclamate as stimuli in a FAL paradigm. Saccharin FAL was observed but cyclamate FAL was not, suggesting that caffeine preexposure selectively potentiated detection of saccharin. In Experiment 4, animals were given saccharin or cyclamate with or without prior exposure to caffeine in a FAL paradigm. During subsequent tests, animals were presented with saccharin or cyclamate following exposure to caffeine saccharin or cyclamate mixed with caffeine saccharin or cyclamate alone. Saccharin FAL was observed following caffeine preexposure, but mixing with caffeine had no effect. These findings of selective potentiation are consistent with previous studies of human sensitivity after caffeine preexposure. Moreover, the present results support the notion that inhibitory A1 adenosine receptors are involved in modulating the perceived intensity of some flavors.

Animals↗
PubMed1996

Conditioned flavour preferences reinforced by caffeine consumed after lunch.

Caffeine-consuming adult males and females were divided into two groups, those who regularly consumed a caffeinated drink after lunch ("users" n = 21) and those who did not ("nonusers" n = 23). After lunch on weekdays during a 2-week conditioning period, these subjects consumed a novel flavoured fruit juice drink paired with either a caffeine (100 mg) or a placebo capsule. Preferences for this "target" drink and six other novel-flavoured fruit juice drinks were assessed before and then after 5 and 10 conditioning trials. The users showed a significantly greater increase in preference for the caffeine-paired target drink than for the placebo-paired target drink, whereas the nonusers showed a slight trend in the opposite direction. These changes in preference did not generalise to the nontarget drink flavours. For habitual postlunch caffeine users, caffeine alleviated the postlunch dip in mood experienced by those in the placebo condition. Thus, the increase in preference for the caffeine-paired target drink was consistent with the improved mood state that resulted from caffeine consumption. It is unlikely, however, that the subjects were aware of this relationship. These results provide strong evidence for the existence of a reinforcing effect of caffeine, which probably plays a significant role in the acquisition of preferences for caffeine-containing drinks.

Adolescent↗
PubMed1987

Alteration of effective exposure of dam and embryo to caffeine and its metabolites by treatment of mice with beta-naphthoflavone.

The effect of treatment of pregnant C57BL/6J (B6) and AKR/J (AKR) mice with the cytochrome P-450 inducing agent beta-naphthoflavone (beta NF) on caffeine metabolism and on exposure of dam and embryo to caffeine and to its metabolites theophylline (TP), theobromine (TB), paraxanthine (PX), and trimethyluric acid (TMUA) was investigated. Treated dams were given either 20 or 80 mg beta NF/kg ip on Days 9 and 10 of gestation. Caffeine, 175 mg/kg, was given ip on Days 11 and 12 of gestation. Concentrations of caffeine and its metabolites were monitored in maternal plasma and in embryo homogenates at 0.083, 0.25, 0.5, 1, 2, 4, and 6 hr after the second caffeine injection. Effective exposure was expressed as the area under the concentration-time curve from 0 to 6 hr. Caffeine loss in B6 mice was best described by an expression incorporating capacity-limited kinetics. Pretreatment induced formation of TB and PX, while it induced elimination of all three of the monodemethylated metabolites, in B6 mice. Consequently, pretreatment caused marked reductions in exposure of B6 dams and embryos to both caffeine and TP. Exposure to TB and PX was less consistently affected, although it was reduced by pretreatment with 80 mg beta NF/kg. In contrast, exposure of AKR dams and embryos to caffeine and its metabolites was only slightly affected by beta NF pretreatment. The prevalence of paw malformations in the offspring of treated mice correlated well with effective exposure to both caffeine and TP, but not at all with the administered caffeine dose.

Animals↗
PubMed1983

Caffeine modification of kindled amygdaloid seizures.

Rats were kindled during exposure to caffeine (50 mg/kg) or saline given IP twenty minutes before daily electrical stimulation of the amygdala until 3 kindled amygdaloid seizures (KAS) occurred. They were then stimulated for 3 days without drug pretreatment followed by 5 additional days with drug pretreatment. There were no significant differences between the two groups in the number of daily stimulations or in the total seconds of cumulative afterdischarge (AD) needed to reach the first KAS. During kindling, the daily average AD tended to be longer in the caffeine treated group. This difference became significant (greater than 200% saline) when the KAS was reached. When KAS animals were stimulated without caffeine pretreatment, the average AD returned to control lengths. When put back on caffeine pretreatment, the average AD was again increased. Caffeine (6-50 mg/kg, IP) was also evaluated in previously kindled rats using suprathreshold (400 mu AMP) and threshold (20 microA increments) seizures. Caffeine had no consistent effect on threshold values. However, 12-50 mg/kg of caffeine increased seizure severity and AD durations after threshold stimulation. With suprathreshold stimulation, the length of the AD was significantly increased only after the highest dose of caffeine. It would appear that caffeine lengthens induced afterdischarges both during the acquisition phase of kindling and in the fully kindled subject. Caffeine does not appear to lower seizure thresholds or increase the rate of acquisition of the KAS in the doses tested in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1988

Reinforcing properties of caffeine: studies in humans and laboratory animals.

Three types of experimental studies are reviewed: (1) intravenous and oral caffeine self-administration by laboratory animals, (2) oral caffeine self-administration by humans, and (3) human subjective effects of caffeine relevant to reinforcing effects. These studies show that, under appropriate conditions, caffeine can serve as a reinforcer and can produce elevations in subjective drug liking and/or euphoria. In this regard, caffeine can be distinguished from a wide range of behaviorally active compounds, such as the amphetamine analog fenfluramine and the major tranquilizer chlorpromazine, which do not produce such effects. Caffeine can also be distinguished from classic drugs of abuse such as cocaine, d-amphetamine or pentobarbital which generally maintain high levels of self-administration (or liking) in contrast to caffeine which tends to maintain lower levels of self-administration (or liking) or maintain self-administration under a more narrow range of parametric conditions. Several human studies and one animal experiment suggest that physical dependence substantially potentiates the reinforcing effects of caffeine. Other human and animal studies indicate that there may be substantial differences between individual subjects in the reinforcing effects of caffeine. An important challenge for future human and animal drug self-administration research will be to delineate more precisely the conditions under which caffeine does and does not serve reliably as a reinforcer.

Animals↗
PubMed1989

Alteration of the effects of caffeine by prenatal stress.

We examined the effect of prenatal stress exposure on sensitivity to caffeine using behavioral and physiological measures. Pregnant rats were handled 5 minutes daily from the 14th to 21st day of gestation. Male offspring were tested when 60 days of age in a modified open field apparatus 30 and 90 minutes after injection with caffeine (0, 10, 30 mg/kg). Caffeine increased crossover frequency and duration at the 10 mg/kg dose. Rearing frequency and duration were increased by the 10 mg/kg dose while the 30 mg/kg dose was ineffective. Gnawing was increased by caffeine, especially 90 minutes postinjection. Headpoke activity was decreased by caffeine treatment. Caffeine had no effect on defecation and urination. Gnawing activity was increased by caffeine in prenatally nonstressed animals, but was depressed in prenatally stressed animals. Prenatal stress increased sensitivity to caffeine on corner activity and rearing. The other measures were not affected differentially by prenatal stress exposure. Rectal temperature was depressed 0.75 degrees C in both prenatally stressed and nonstressed animals, by the 30 mg/kg dose of caffeine. Thus, our results indicate that prenatal stress affects sensitivity to caffeine in the adult offspring. However, the long-term effects of prenatal stress exposure are dependent on the measures employed.

Animals↗
PubMed1989

Caffeine and cigarette smoking: behavioral, cardiovascular, and metabolic interactions.

Coffee drinking and cigarette smoking are strongly correlated behaviors which have been suggested to act synergistically to produce adverse health consequences, particularly coronary heart disease (CHD). We studied in smokers the influence of four days of multiple daily doses of coffee containing different doses or no caffeine on cigarette smoking behavior, nicotine intake from smoking, heart rate and blood pressure, circadian serum glucose, and urinary catecholamine excretion. We observed a tendency toward greater cigarette consumption during caffeine consumption, and a tendency toward higher plasma nicotine levels during low-dose caffeine compared with the no-caffeine condition; however, these effects were small. No caffeine effects on any other of the above parameters were observed. Previously published research has usually studied effects of single doses of caffeine, which does not account for development of tolerance to effects of caffeine. If caffeine does contribute to CHD risk, it is not likely to be related to caffeine effects on smoking behavior, nicotine intake, blood pressure, heart rate, glucose tolerance, or catecholamine release. Adverse effects of long-term caffeine consumption on lipids cannot be excluded.

Adult↗
PubMed1991

Neonatal caffeine exposure alters developmental sensitivity to adenosine receptor ligands.

Studies were done to determine whether the apparent changes in behavioral sensitivity to adenosine receptor ligands that occur with age and with neonatal caffeine exposure were due to a change in sensitivity of the receptor for the ligand or to a more fundamental change in the receptor. Using an animal model that mimics the brain developmental period and level of caffeine exposure in human premature neonates treated with caffeine for apnea of prematurity, behavioral and neurochemical investigations were undertaken. The locomotor responses to acute challenge with caffeine (15, 30 and 60 mg/kg) and with D-phenylisopropyladenosine (D-PIA) (0.038 and 0.38 mg/kg), an adenosine receptor agonist, were measured in control and neonatally caffeine-exposed rats at 12, 15, 18, and 28 days of age. The dissociation constants (Kd) and maximal binding densities (Bmax) for agonist binding at the adenosine A1 receptor site were determined over a similar time period. Caffeine displacement of an adenosine A1 agonist was also measured to examine in vitro sensitivity to caffeine as a function of age and neonatal caffeine exposure. Our studies demonstrated that the differential responses to adenosine receptor ligands seen as a function of both age and neonatal caffeine exposure could not be overcome by merely increasing the doses of ligand administered. In addition, the results of the binding studies indicated that changes in the adenosine receptor are occurring as a function of age in different regions of the brain of control animals and that this development is influenced by neonatal caffeine exposure.

Adenosine↗