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PubMed1994

Interactions of opioids with caffeine: evaluation by ambulatory activity in mice.

Morphine (up to 10 mg kg-1), buprenorphine (up to 0.1 mg kg-1), pentazocine (30 mg kg-1) and caffeine (up to 10 mg kg-1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D1- and D2-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0.1-3 mg kg-1) itself did not change mouse ambulation, at 3 mg kg-1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg-1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg-1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg-1) with buprenorphine (0.3 mg kg-1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg-1) by the repeated treatment with buprenorphine (0.3 mg kg-1) was inhibited by caffeine (10 mg kg-1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on mu- or sigma-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.

Animals↗
PubMed1968

The action of caffeine on the activation of the contractile mechanism in straited muscle fibres.

1. The effect of caffeine on the initiation of isometric tension in isolated twitch muscle fibres of the frog was recorded with a mechano-electrical transducer.2. In Ringer solution as well as in solutions containing 95 mM-K(2)SO(4), caffeine (6-10 mM) caused reversible contractures. Tension of maximal potassium contractures was reached with a half-time of 2-4 sec.3. Caffeine caused a shift to lower potassium concentrations of the S-shaped curve which relates peak tension to log. [K](o) or membrane potential. In subthreshold concentrations of caffeine (1.5 mM) the potassium concentration at which half of maximal tension was reached shifted from 30 to 16 mM-K (-39 to -53 mV).4. In the ;steady state' the ability of fibres to develop tension is related to log. [K](o) or membrane potential by an S-shaped curve whose half value shifted from 28 to 45 mM-K (-41 to -29 mV) when 1.5 mM caffeine was applied.5. Fibres were most sensitive to caffeine at membrane potentials between -50 and -20 mV.6. The mechanical activity caused by caffeine was ;stabilized' by an increase in [Ca](o) or [Mg](o) resembling the stabilizing action of these ions on potassium contractures or on the sodium permeability of excitable membranes.7. Tetracaine in low concentrations (0.04-0.1 mM) increased the threshold for mechanical activation and shortened the plateau of potassium contractures. Higher concentrations (1-2 mM) suppressed mechanical activity completely.8. Tetracaine, 0.04 mM, was sufficient to suppress tension caused by a 100 times stronger concentration of caffeine. With higher concentrations of caffeine the inhibitory action of tetracaine could be reversed.9. Fibres which were immersed in subthreshold concentrations of caffeine either in Ringer solution or in a solution with 95 mM-K(2)SO(4) developed a strong contracture after a sudden drop in temperature from 20 to 1-3 degrees C.10. The fast activation of the whole cross-section of the muscle fibre caused by caffeine and its dependence on membrane potential, tetracaine and external alkali earth ions favours the idea that the drug acts at some part of the sarcotubular system which is easily accessible for external ions and drugs and in close connextion with the surface membrane.

Animals↗
PubMed1992

A caffeine- and ryanodine-sensitive Ca2+ store in bullfrog sympathetic neurones modulates effects of Ca2+ entry on [Ca2+]i.

1. We studied how in changes in cytosolic free Ca2+ concentration ([Ca2+]i) produced by voltage-dependent Ca2+ entry are influenced by a caffeine-sensitive Ca2+ store in bullfrog sympathetic neurones. Ca2+ influx was elicited by K+ depolarization and the store was manipulated with either caffeine or ryanodine. 2. For a time after discharging the store with caffeine and switching to a caffeine-free medium: (a) [Ca2+]i was depressed by up to 40-50 nM below the resting level, (b) caffeine responsiveness was diminished, and (c) brief K+ applications elicited [Ca2+]i responses with slower onset and faster recovery than controls. These effects were more pronounced as the conditioning caffeine concentration was increased over the range 1-30 mM. 3. [Ca2+]i, caffeine and K+ responsiveness recovered in parallel with a half-time of approximately 2 min. Recovery required external Ca2+ and was speeded by increasing the availability of cytosolic Ca2+, suggesting that it reflected replenishment of the store at the expense of cytosolic Ca2+. 4. During recovery, Ca2+ entry stimulated by depolarization had the least effect on [Ca2+]i when the store was filling most rapidly. This suggests that the effect of Ca2+ entry on [Ca2+]i is modified, at least in part, because some of the Ca2+ which enters the cytosol during stimulation is taken up by the store as it refills. 5. Further experiments were carried out to investigate whether the store can also release Ca2+ in response to stimulated Ca2+ entry. In the continued presence of caffeine at a low concentration (1 mM), high K+ elicited a faster and larger [Ca2+]i response compared to controls; at higher concentrations of caffeine (10 and 30 mM) responses were depressed. 6. Ryanodine (1 microM) reduced the rate at which [Ca2+]i increased with Ca2+ entry, but not to the degree observed after discharging the store. At this concentration, ryanodine completely blocked responses to caffeine but had no detectable effect on Ca2+ channel current or the steady [Ca2+]i level achieved during depolarization. 7. We propose that, depending on its Ca2+ content, the caffeine-sensitive store can either attenuate or potentiate responses to depolarization. When depleted and in the process of refilling, the store reduces the impact of Ca2+ entry as some of the Ca2+ entering the cytosol during stimulation is captured by the store.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Caffeine enhances intramembranous charge movement in frog skeletal muscle by increasing cytoplasmic Ca2+ concentration.

1. Currents of intramembranous charge movement were recorded, together with intracellular [Ca2+], in single muscle fibres subjected to voltage-clamp depolarization and 'pulses' of extracellular solution with a Ca2+ release-inducing concentration of caffeine (10 mM). 2. When caffeine was present prior to and during the voltage pulses, the charge transferred by pulses to between -60 and -40 mV increased by about 40%. 3. In fibres depleted of Ca2+ in the sarcoplasmic reticulum (SR), caffeine had no effect on charge transfer or kinetics. 4. Whenever the prior exposure to caffeine resulted in a large elevation in [Ca2+]i at the start of the depolarizing pulse, there was an increase in I beta, the monotonically decaying component of charge movement. When the presence of caffeine enhanced Ca2+ release induced by the pulse, there was increase in I gamma, the hump-like component. 5. The charge transferred during a pulse to -50 mV increased with time of exposure to caffeine. Ca2+ release induced by the voltage pulse grew during the first second of caffeine exposure, then decreased with longer exposure time. The enhancement of charge transfer by caffeine was therefore not due to the increase in Ca2+ release caused by the drug. 6. The increase in charge transfer was a uniform, monotonically increasing function of the [Ca2+]i attained at the end of the voltage pulse. 7. Charge transfer, as a function of [Ca2+]i, pulse voltage and time, was simulated with a model, used previously, in which Ca2+ binds to intracellular sites and increases the electrical potential near the voltage sensors. Two sites were needed to fit the observations, with dissociation constants of 60 nM and 2 to 10 microM. 8. In the presence of caffeine, the voltage-driven movement of a given amount of intra-membranous charge resulted in greater activation of release permeability. 9. All effects of caffeine observed in this and the preceding paper could be explained assuming a single action: caffeine increases the tendency of the release channels to open. This results in opening of closed channels and an increase in their susceptibility to activation by the voltage sensors.

Animals↗
PubMed1992

Rat atrial muscle responses with caffeine: dose-response, force frequency, and postrest contractions.

Caffeine has been reported to have a positive and (or) a negative inotropic effect on cardiac muscle. In this study, the force-frequency and postrest characteristics of rat atrium were studied in the presence of caffeine (1.0-10 mM) to see if the interval between beats affected the response of cardiac muscle to caffeine. When stimulation frequency was 0.5 or 2.0 Hz, there was a positive followed by a negative inotropic response with 1, 5, or 10 mM caffeine. Incomplete relaxation occurred under these circumstances, giving rise to contracture. At low frequency of stimulation (0.1 Hz) caffeine had only a negative inotropic effect, and this effect was greater with 1 mM caffeine than with 5 mM caffeine. In the absence of caffeine, when stimulation at 0.5 or 3 Hz was interrupted, a pause of 2-20 s resulted in potentiation. When caffeine was present (2.0 mM), postrest potentiation was severely attenuated, but the steady-state contraction amplitude within the range 0.5-3.0 Hz was not different. These results are consistent with the hypothesis that caffeine induces a leak of Ca2+ from the sarcoplasmic reticulum, and this Ca2+ is extruded from the cell, possibly by Na+/Ca2+ exchange. Sarcoplasmic reticular uptake of Ca2+ and the translocation to release sites appear not to be affected by caffeine within 1-5 mM concentrations.

Animals↗
PubMed1975

Contractures in partially depolarized muscle treated with caffeine or nitrate.

Frog toe muscles partially depolarized with a subcontracture concentration (15 or 20mM) of K+ rapidly developed tension when exposed to 1 mM caffeine, which alone did not cause contracture. This action resulted from a lowering of the mechanical threshold by the caffeine and thus was similar to that caused by replacement of Cl- with NO3-. Maximal tension was the same in the caffeine and NO3- media but took much longer to develop in the former. Equilibrating the muscles with caffeine for 60 s (the time calculated for complete diffusion) did not reduce contraction time significantly. However, prolonging the exposure of muscles to caffeine beyond this time enhanced the drug's capacity to potentiate both the twitch and 30 mM K+ contractures and shortened the contraction time of the contractures. Toe muscles that had undergone a contracture in 100 mM K+ and were recovering in 15 mM K+-Ringer generated tension in the presence of 1 mM caffeine or NO3- but only after enough repolarization had been achieved so that a response to a second challenge with 100 mM K+ could be demonstrated. Although prolonged immersion in the K+-enriched recovery solution caused a disappearance of sensitivity to a test depolarization, addition of 1 mM caffeine or replacement of Cl- with NO3- promptly evoked a contracture. These results imply a reversible step in the recovery process that is both potential and time dependent. Since application of 5 mM caffeine to either normally polarized or depolarized muscles always immediately causes contracture, more than one site of action for caffeine is indicated. After disruption of the transverse tubules, partially depolarized muscles showed no response to NO3- or 1 mM caffeine but contracted vigorously when exposed to 5 mM caffeine.

Action Potentials↗
PubMed1992

Acute and habitual caffeine ingestion and metabolic responses to steady-state exercise.

This study compared the exercise catecholamine and metabolic responses to a caffeine challenge in trained subjects before and after a 6-wk period of increased caffeine ingestion. Trained subjects (n = 6) were challenged with 500 mg of caffeine followed by prolonged exercise before and after 6 wk of increased caffeine ingestion (500 mg ingested before each daily run). A control group (n = 6) of trained subjects followed the same protocol except for caffeine ingestion. Acute caffeine ingestion resulted in increased plasma epinephrine and decreased respiratory exchange ratio (RER) during exercise. After 6 wk of caffeine supplementation, the epinephrine response to exercise or caffeine plus exercise was decreased, although the latter still resulted in a lower RER value compared with exercise without caffeine ingestion. Activity of key metabolic enzymes (hexokinase, citrate synthase, phosphorylase, and 3-hydroxyacyl-coenzyme A dehydrogenase) from biopsies of the gastrocnemius showed no response to 6 wk of this increased adrenergic receptor stimulation and, on the basis of the lower RER, enhanced fat metabolism. This study suggests that caffeine ingestion by trained subjects causes increases in plasma epinephrine and reduces the RER during exercise. However, habitual stimulation results in a general dampening of the epinephrine response to caffeine or exercise. There was no indication that increased adrenergic stimulation and fat oxidation caused any adaptation in the activity of metabolic enzymes.

Adult↗
PubMed2004

Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption.

Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial. Individual differences in tolerance formation were then examined. Men (n=49) and women (n=48) completed a double-blind, crossover trial conducted over 4 weeks. During each week, subjects abstained for 5 days from dietary caffeine and instead used capsules totaling 0 mg, 300 mg, and 600 mg of caffeine per day in 3 divided doses. On day 6, in the laboratory, they used capsules with either 0 mg or 250 mg of caffeine at 9:00 am and 1:00 pm. Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant (P<0.006/0.001) at all levels of previous daily consumption. Individual difference comparisons found that although half the subjects had complete loss of systolic and diastolic BP responses to the challenge doses, the other half showed no loss in BP response, even after using 600 mg of caffeine per day for the previous 5 days (F >7.90, P <0.001). The sexes did not differ in degree of tolerance formation. Daily caffeine consumption failed to eliminate the BP response to repeated challenge doses of caffeine in half of the healthy adults who were tested. Caffeine may therefore cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels.

Adult↗
PubMed2002

Topographic quantitative EEG response to acute caffeine withdrawal: a comprehensive analysis of multiple quantitative variables.

Most previous studies of the neurophysiological effects of caffeine have focused on the effects of caffeine ingestion, and few studies have examined the effects of caffeine withdrawal. This open study evaluated the quantitative EEG (QEEG) changes occurring during a 4-day period of abstinence in subjects who habitually consume 300 mg or more of caffeine daily. Thirteen subjects underwent QEEG studies during their usual caffeine consumption (baseline) and on days 1, 2, and 4 of a 4-day period of caffeine abstinence. Ten of the subjects underwent a second QEEG on day 4 that consisted of a period of recording after reinstitution of caffeine. A comprehensive analysis of multiple quantitative variables was performed for each study during the abstinence period and compared to the variables obtained at baseline for each subject. Changes occurring during caffeine abstinence included: 1) increases in theta absolute power over all cortical areas, 2) increases in delta absolute power over the frontal cortex, 3) decreases in the mean frequency of both the alpha and beta rhythm, 4) increase in theta relative power and decrease in beta relative power, and 5) significant changes in interhemispheric coherence. Most of these changes tended to return to pre-abstinence baseline levels rapidly after resumption of caffeine consumption. The caffeine withdrawal state affects a number of neurophysiological variables. Further investigation of the neurophysiological aspects of caffeine withdrawal using placebo controlled double blind assessment methods is warranted.

Adolescent↗
PubMed1994

Chronic effects of habitual caffeine consumption on laboratory and ambulatory blood pressure levels.

BACKGROUND: Uncertainty continues to surround the role of habitual caffeine consumption as a cardiovascular risk factor. The present study examined the effects of moderate caffeine intake on 24h blood pressure and heart rate in normotensive men and women. METHODS: A double-blind, placebo-controlled, crossover design with counterbalancing was used, in which 36 healthy men and women participated in four experimental conditions involving the ingestion of placebo or caffeine three times daily for 6 days, followed by a seventh ('challenge') day of placebo or caffeine ingestion. RESULTS: When caffeine was consumed on the challenge day, blood pressure was found to be elevated immediately after caffeine ingestion and was either unchanged or decreased (hypotensive effect) after a period of abstinence from the drug. Some diminution of the peak pressor effects was found when participants ingested caffeine after habitual use of the drug (6.0/5.2 mmHg) compared with when they had been abstinent before the challenge day (7.7/6.8 mmHg). This diminution in the reaction was comparatively small, however, and pressor effects persisted on caffeine-challenge days even when caffeine was consumed on preceding days. CONCLUSION: Habitual consumption diminished, but did not eliminate, the pressor effects of caffeine. Considering the almost universal consumption of caffeine beverages, the persistent pressor effects of the drug could have important implications for cardiovascular health.

Adolescent↗
PubMed2003

Caffeine impairs short-term neurological outcome after concussive head injury in rats.

OBJECTIVE: Adenosine is an endogenous neuroprotective agent that is released during ischemia, hypoxia, epilepsy, and ischemic brain injury. Caffeine is a receptor antagonist for adenosine that might interfere with the neuroprotective effect of adenosine in ischemic-hypoxic conditions. An investigation was undertaken to study the effect of caffeine on neurological function, edema formation, and blood-brain barrier permeability after experimental head injury in rats. METHODS: Adult female Wistar rats classified into different groups received caffeine intraperitoneally at doses of 0, 50, 100, and 150 mg/kg body weight. Thirty minutes after the caffeine treatment, the animals were subjected to concussive head injury (CHI) administered by a controlled cortical impact device. Neurological severity score was recorded in each rat at 2 hours after CHI. Specific gravity, water content (as an indicator of edema), and blood-brain barrier impairment were analyzed in the cortical tissue surrounding the injury site. The levels of myeloperoxidase and malondialdehyde in the cortical region were measured as indicators of neutrophil infiltration and lipid peroxidation, respectively. RESULTS: A significant increase in righting latency and neurological deficiency after CHI was observed in caffeine-treated rats as compared with untreated animals. Although no deaths occurred in the rats exposed to CHI after pretreatment with saline, pretreatment with caffeine caused significant mortality of animals after trauma in a dose-dependent manner. Caffeine also exacerbated neutrophil infiltration, edema, and disruption of blood-brain barrier in the traumatic cortex. Light microscopy of brain revealed more severe hemorrhage and neuronal degeneration in the injured hemisphere of caffeine-treated rats as compared with rats in the injury-alone group. A significant increase in malondialdehyde in the brain of injured rats treated with caffeine before CHI clearly indicated the role of oxidative stress. CONCLUSION: Caffeine adversely affects outcome after CHI, possibly as a result of blockade of adenosine receptors. The findings also point toward the involvement of free radical-mediated neuronal damage in caffeine-induced exacerbation of neurotrauma.

Animals↗
PubMed1992

Application of microdialysis for study of caffeine distribution into brain and cerebrospinal fluid in rats.

The usefulness of microdialysis was examined for the chronological determination of caffeine concentration in the brain and cerebrospinal fluids (CSF) following intravenous administration of caffeine in rats. The recovery percent of caffeine by microdialysis, the concentration ratio of caffeine in the dialysate against that in the brain tissue or CSF was determined. The recovery percent was proved to be constant at 5 different steady-state plasma concentrations of caffeine (0.1-280 nmol/ml) and in different collecting periods of dialysate ranging from 30 s to 10 min. The mean recovery percent in the brain and CSF were 10.9 and 13.1%, respectively. Thus, microdialysis was proved useful for determination of drug concentration in the tissue and biological fluids with time resolution of more than 30 s. The microdialysis method was then applied for the chronological determination of caffeine concentration in the brain and CSF following intravenous bolus administration. The estimated caffeine concentration in the brain and CSF was the same as those obtained by direct determination in isolated brain and CSF, respectively. Transfer of caffeine from plasma to brain and CSF were further pharmacokinetically analyzed using a modified 2-compartment model. In this kinetic model, the transfer of caffeine between the CSF and brain was neglected, since the mutual transfer of caffeine was not detected in in vivo experiments. Calculated curves were well fitted on observed caffeine concentrations in the plasma, brain and CSF.

Animals↗
PubMed1988

High-dose caffeine and cardiac rate and rhythm in normal subjects.

In a previous 24-hour study of the electrophysiologic effects of moderate dose caffeine (1 mg/kg body weight/half-life), we found a significant (p less than 0.01) increase in ventricular ectopic beat (VEB) frequency among 18 patients with preexisting primary ventricular dysrhythm (mean 207 +/- 350 VEBs/hour, no caffeine, versus 307 +/- 414 VEBs/hour, caffeine). We also found a statistically insignificant (NS) increase in the incidence of infrequent VEBs in 18 normal control subjects (four of 18, no caffeine vs nine of 18 caffeine). Because of the high risk of beta-error among the previously-studied normal control subjects, we tested another group of 34 normal subjects, 15 males and 19 females with a mean age of 31 years (range 21 to 49 years), using a higher dose of caffeine. All subjects abstained from caffeine for 72 hours and had a control 24-hour Holter ECG recorded between hours 48 and 72. Caffeine half-life was calculated for each subject and caffeine was then ingested at 1 mg/kg every 0.5 half-life during all waking hours. A 24-hour Holter test was recorded, beginning just prior to the second caffeine dose. It was concluded that in normal adults, even high-dose caffeine does not affect prevailing cardiac rhythm and rate, and moreover, does not cause clinically significant ventricular or supraventricular dysrhythm.

Adult↗
PubMed2000

Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study.

STUDY OBJECTIVE: To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity. DESIGN: Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue. SETTING: Nine neonatal intensive care units. PATIENTS: Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours. INTERVENTION: Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue. MEASUREMENTS AND MAIN RESULTS: Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate. CONCLUSION: Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception.

Apnea↗
PubMed1978

Caffeine contracture in transverse tubules-disrupted fiber and effect of anomalous anions on the contracture in frog twitch fiber.

Caffeine contracture in transverse tubules-disrupted (T-disrupted) muscle preparation and the effect of anomalous anions (SCN and NO3) on the contracture in single twitch fibers or thin bundles consisting of 2 or 3 fibers of frog were investigated. The magnitude and the rate of rise of caffeine contracture tension were decreased by T-disruption and the decrease was more marked at lower concentrations of caffeine. No seasonal difference between summer and winter frogs on the effect of T-disruption on caffeine contracture was observed. On the other hand, the magnitude and the rate of rise of caffeine contracture tension in the intact preparation was increased by anomalous anions, whereas the rate of spontaneous relaxation of the contracture was decreased. The effect of SCN on caffeine contracture appeared 5 min after the pre-exposure of muscle preparation of SCN-Ringer solution, with the maximal effect appearing after 10 min. The threshold curve of caffeine contracture was shifted toward the lower caffeine concentrations by anomalous anions and the extent of the shift in the curve was more pronounced with SCN than with NO2. In contrast, the potentiating effect of these anions on the caffeine contracture completely disappeared in T-disrupted muscle preparation. On the basis of these results, the caffeine pathway to the sarcoplasmic reticulum, and the sites and mechanism of the action of anomalous anions on caffeine contracture are discussed.

Animals↗
PubMed2002

Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise.

We investigated the effects of caffeine ingestion on skeletal muscle glucose uptake, glycogen synthase (GS) activity, and insulin signaling intermediates during a 100-min euglycemic-hyperinsulinemic (100 microU/ml) clamp. On two occasions, seven men performed 1-h one-legged knee extensor exercise at 3 h before the clamp. Caffeine (5 mg/kg) or placebo was administered in a randomized, double-blind fashion 1 h before the clamp. During the clamp, whole-body glucose disposal was reduced (P < 0.05) in caffeine (37.5 +/- 3.1 micromol x min(-1) x kg(-1)) vs. placebo (54.1 +/- 2.9 micromol x min(-1) x kg(-1)). In accordance, the total area under the curve over 100 min (AUC(0--100 min)) for insulin-stimulated glucose uptake in caffeine was reduced (P < 0.05) by approximately 50% in rested and exercised muscle. Caffeine also reduced (P < 0.05) GS activity before and during insulin infusion in both legs. Exercise increased insulin sensitivity of leg glucose uptake in both caffeine and placebo. Insulin increased insulin receptor tyrosine kinase (IRTK), insulin receptor substrate 1-associated phosphatidylinositol (PI) 3-kinase activities, and Ser(473) phosphorylation of protein kinase B (PKB)/Akt significantly but similarly in rested and exercised legs. Furthermore, insulin significantly decreased glycogen synthase kinase-3alpha (GSK-3alpha) activity equally in both legs. Caffeine did not alter insulin signaling in either leg. Plasma epinephrine and muscle cAMP concentrations were increased in caffeine. We conclude that 1) caffeine impairs insulin-stimulated glucose uptake and GS activity in rested and exercised human skeletal muscle; 2) caffeine-induced impairment of insulin-stimulated muscle glucose uptake and downregulation of GS activity are not accompanied by alterations in IRTK, PI 3-kinase, PKB/Akt, or GSK-3alpha but may be associated with increases in epinephrine and intramuscular cAMP concentrations; and 3) exercise reduces the detrimental effects of caffeine on insulin action in muscle.

Adult↗
PubMed1988

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.

Animals↗
PubMed1999

The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions.

We sought neurochemical correlates to the stimulatory action of caffeine in rats and to adaptations during development of tolerance. Acute intraperitoneal injections of caffeine (7.5 mg/kg) increased locomotion and NGFI-A mRNA, a marker of neuronal activity, in the hippocampal area CA1, but decreased NGFI-A mRNA in rostral striatum and nucleus accumbens. Rats that received caffeine (0.3 gm/l) in their drinking water for 14 d developed tolerance to the stimulatory effect of a challenge with caffeine (7.5 mg/kg) and responded with a less pronounced decrease of NGFI-A mRNA in rostral striatum and nucleus accumbens. Metabolism of caffeine to its active metabolites was increased in tolerant animals, but the total level of active metabolites in brain was not significantly altered. Thus, there are changes in caffeine metabolism after long-term caffeine treatment, but they cannot explain development of tolerance. Caffeine-tolerant animals had downregulated levels of adenosine A2A receptors and the corresponding mRNA in rostral parts of striatum, but an increased expression of adenosine A1 receptor mRNA in the lateral amygdala. No changes in mesencephalic tyrosine hydroxylase mRNA were found in caffeine-tolerant rats. Thus, we have identified neuronal pathways that are regulated by adenosine A1 and/or A2A receptors and are targets for the stimulatory action of caffeine. Furthermore, adaptive changes in gene expression in these brain areas were associated with the development of locomotor tolerance to caffeine.

Animals↗