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At least 793 records · Page 44Linked to original sources
PubMed1997

Caffeine and chronic back pain.

OBJECTIVE: Tobacco use and other behavioral factors are associated with chronic back pain. Anecdotes suggest excess caffeine use may also be associated with chronic back pain. We compared caffeine consumption by chronic back pain patients with caffeine consumption by controls. DESIGN: Retrospective case-control study. SETTING: A multispecialty outpatient facility. PATIENTS: Sixty new, consecutive patients with chronic back pain compared to 60 new, consecutive patients without chronic back pain. INTERVENTION: Patients were prospectively asked to complete an intake questionnaire. MAIN OUTCOME MEASURE: Daily caffeine consumption was estimated by analyzing the intake questionnaire. Differences between groups were analyzed by both normal and nonparametric statistics. RESULTS: Consumption of caffeine by patients with chronic back pain averaged 392.4 mg/day. Controls consumed 149.8 mg/ day, a significant difference (p = .0001). Men consumed 86% more caffeine per day than women (p = .02). Age and caffeine consumption showed little correlation (r = .126). CONCLUSIONS: Patients with chronic back pain consume over twice as much caffeine as patients without chronic back pain. Confounding variables and possible mechanisms associating caffeine with chronic back pain are discussed.

Adult↗
PubMed1989

Caffeine slows turn-off of calcium release in voltage clamped skeletal muscle fibers.

Myoplasmic free calcium transients delta [Ca2+] were monitored with the calcium indicators antipyrylazo III and fura-2 in voltage clamped cut frog skeletal muscle fibers, in the presence and absence of 0.5 mM caffeine. Without caffeine delta [Ca2+] began to decline within a few milliseconds of fiber repolarization for pulses of all durations. In caffeine delta [Ca2+] continued to rise for 10-60 ms after 10 or 20 ms depolarizing pulses, indicating that the release of calcium from the sarcoplasmic reticulum (SR) continued well after repolarization of transverse tubular (TT) membranes in the presence of caffeine. Caffeine also increased the peak amplitude of delta [Ca2+] for all pulses and slowed the decline of delta [Ca2+] after pulses of all durations. The rate of calcium release from the SR calculated from delta [Ca2+] showed that for 10 ms pulses in caffeine release did not turn off abruptly on repolarization but instead declined to zero with a time constant essentially the same as the time constant for inactivation of SR calcium release during depolarizing pulses in the presence or absence of caffeine. The observed loss of TT membrane potential control of SR calcium release in the presence of caffeine suggests the appearance of a significant component of cytosolic Ca2+-induced calcium release in caffeine.

Animals↗
PubMed1996

The effect of liver disease on urine caffeine metabolite ratios.

OBJECTIVES: A number of caffeine metabolite ratios (CMRs) have been proposed to measure CYP1A2 activity in vivo. The effect of liver disease on these ratios is not clear. The objective of this study was to determine the influence of liver disease on caffeine metabolite ratios. STUDY DESIGN: Two studies were performed. First, in healthy control subjects and in subjects with cirrhosis, caffeine clearance was measured by intravenous infusion of stable isotope-labeled caffeine while subjects consumed oral caffeine. Second, spot urine samples were collected from control subjects and from subjects with either chronic hepatitis or cirrhosis while they consumed caffeine. RESULTS: In study 1, caffeine clearance was decreased in subjects with cirrhosis (control mean, 0.14 L/hr/kg; cirrhosis mean, 0.04 L/hr/kg; p = 0.003). CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2; p = 0.005). AAMU + 1X + 1U/17U correlated significantly with caffeine clearance in the control group (r2 = 0.68; p = 0.0001) and in subjects with cirrhosis (r2 = 0.41; p = 0.05). In study 2, there was a significant difference between control subjects and subjects with cirrhosis for AAMU + 1X + 1U/17U (median for control subjects, 6.2; median for subjects with cirrhosis, 4.3; p = 0.001) but not between control subjects and patients with chronic hepatitis. CONCLUSIONS: We conclude that AAMU + 1X + 1U/17U is affected by liver disease and reflects the decrease in CYP1A2 activity in subjects with cirrhosis. AAMU + 1X + 1U/17U measured from a spot urine sample reflects caffeine clearance in subjects with cirrhosis and may be useful as a hepatic function test. Despite the large interindividual variation observed, the test can be repeated easily in the same patient and an individual patient's decline in CYP1A2 activity, such as in patients with progressively deteriorating liver function, can be monitored.

Adult↗
PubMed1999

Scopolamine prevents tolerance to the effects of caffeine on rotational behavior in 6-hydroxydopamine-denervated rats.

Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects. In this study, using unilateral 6-hydroxydopamine nigrostriatal denervated rats, we tested the hypothesis that the muscarinic receptor antagonist, scopolamine, would prevent the tolerance to caffeine-induced contralateral rotational behavior. For that purpose we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior.

Animals↗
PubMed1984

On the mechanism by which caffeine abolishes the fast rhythms induced by cardiotonic steroids.

The abolition by caffeine of the arrhythmias induced by cardiotonic steroids was studied in canine Purkinje and ventricular muscle fibers and in guinea pig ventricular muscle perfused in vitro. Both the electrical and mechanical activity were recorded. The following results were obtained: (1) Caffeine (9 mM) quickly abolished the arrhythmias induced by strophanthidin (10(-6)M) in Purkinje fibers by inducing quiescence at a depolarized level; (2) A lower concentration of caffeine (3 mM) hastened the appearance of the arrhythmias by favoring the onset of spontaneous activity at a depolarized level but abolished the oscillatory potential at lower strophanthidin concentrations (2-5 X 10(-7)M); (3) Caffeine (9-10 mM) abolished the oscillatory potentials and after-contractions induced by cardiotonic steroids in ventricular muscle fibers; (4) Caffeine prevented the induction of oscillatory potentials and of arrhythmias by cardiotonic steroids; (5) In the presence of cardiotonic steroids and norepinephrine, the oscillatory potentials can induce fast discharge in myocardial fibers which is eliminated by caffeine; (6) High calcium and norepinephrine (singly or together) induce oscillatory potentials and after-contractions which are abolished by caffeine; (7) The elimination of the oscillatory potentials by caffeine in myocardial fibers is associated with the development of contracture. It is concluded that caffeine eliminates cardiac steroid-induced arrhythmias by quickly depolarizing Purkinje fibers and by eliminating the oscillatory potentials in myocardial fibers and (at suitable concentrations) also in Purkinje fibers.

Action Potentials↗
PubMed1984

Effects of low sodium perfusion on cardiac caffeine sensitivity and calcium uptake.

Myocardial compartmentation of calcium was investigated in the arterially perfused rabbit interventricular septum under conditions of augmented calcium uptake. Reduction of perfusate sodium concentration (100-36 mM [Na]0) produced the expected increased active force development and an increased myocardial calcium content that was inversely proportional to [Na]0. Caffeine was used to inhibit calcium uptake by the sarcoplasmic reticulum (SR) and to stimulate SR calcium release. The diastolic tension response to caffeine was also inversely proportional to [Na]0: at [Na]0 of 139 mM, 10 mM caffeine increased diastolic tension by 20%; whereas at 36 mM [Na]0 diastolic tension increased by 205%. The increase in diastolic tension in response to caffeine was considered a reflection of increased cytosolic calcium. The increase in diastolic tension with caffeine required that reduced [Na]0 be present at the time caffeine was administered. Caffeine sensitivity (measured by an increase in diastolic tension) and active force development declined to control levels within 3 minutes after the end of a 40 minute period of low [Na]0 perfusion despite the presence of an additional 1 mmole calcium per kg dry wt in the muscle at the 3 minute mark when caffeine was added. The results indicate that low [Na]0 perfusion induces an increment in myocardial calcium content, a major fraction of which is neither related directly to contractility nor involved in the response to caffeine.

Animals↗
PubMed2003

Stimulatory effect of oral administration of green tea and caffeine on locomotor activity in SKH-1 mice.

Administration of green tea or caffeine was shown previously to inhibit ultraviolet B light-induced carcinogenesis in SKH-1 mice, and this effect was associated with a reduction in dermal fat. In the present study, oral administration of 0.6% green tea (6 mg tea solids/ml) or 0.04% caffeine (0.4 mg/ml; equivalent to the amount of caffeine in 0.6% green tea) as the sole source of drinking fluid to SKH-1 mice for 15 weeks increased total 24 hr locomotor activity by 47 and 24%, respectively (p<0.0001). Oral administration of 0.6% decaffeinated green tea (6 mg tea solids/ml) for 15 weeks increased locomotor activity by 9% (p<0.05). The small increase in locomotor activity observed in mice treated with decaffeinated green tea may have resulted from the small amounts of caffeine still remaining in decaffeinated green tea solutions (0.047 mg/ml). The stimulatory effects of orally administered green tea and caffeine on locomotor activity were paralleled by a 38 and 23% increase, respectively, in the dermal muscle layer thickness. In addition, treatment of the mice with 0.6% green tea or 0.04% caffeine for 15 weeks decreased the weight of the parametrial fat pad by 29 and 43%, respectively, and the thickness of the dermal fat layer was decreased by 51 and 47%, respectively. These results indicate that oral administration of green tea or caffeine to SKH-1 mice increases locomotor activity and muscle mass and decreases fat stores. The stimulatory effect of green tea and caffeine administration on locomotor activity described here may contribute to the effects of green tea and caffeine to decrease fat stores and to inhibit carcinogenesis induced by UVB in SKH-1 mice.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Diazepam alters caffeine-induced effects on beta-endorphin levels in specific rat brain regions.

The present study was conducted to evaluate the effects of caffeine and the benzodiazepine agonist diazepam, and a combination of both on beta-endorphin (beta-EN) levels in specific rat brain regions. Male Sprague-Dawley rats (150-200 g) adapted to a 12-hour light: 12-hour dark illumination cycle were used in this study. Caffeine (10 mg/kg), diazepam (2 mg/kg) or a combination of caffeine (10 mg/kg) and diazepam (2 mg/kg) were administered intraperitoneally to rats at 11:00 hr. Control animals were injected with saline. Animals were sacrificed by decapitation 1 h after injection, the brains were immediately removed; the cortex, hippocampus, hypothalamus and midbrain were dissected and their B-EN levels measured by radioimmunoassay. Caffeine administration significantly increased B-EN levels in the cortex. Similarly, administration of diazepam alone resulted in a significant increase of B-EN levels in cortex. However, concurrent administration of diazepam and caffeine resulted in higher increase of B-EN levels in cortex. No significant changes in B-EN levels were detected in hippocampus and midbrain after administration of either caffeine or diazepam alone. On the other hand, when diazepam and caffeine were concurrently administered a significant increase of B-EN levels were observed in the midbrain. Moreover, administration of diazepam alone resulted in a significant increase of B-EN levels in hypothalamus. This increase was still observed following concurrent administration of diazepam and caffeine. These results clearly indicate that diazepam alters caffeine-induced effects on B-EN in specific rat brain regions.

Animals↗
PubMed2000

Caffeine-induced increases in the brain and plasma concentrations of neuroactive steroids in the rat.

The effects of caffeine, a naturally occurring stimulant, on the brain and plasma concentrations of neuroactive steroids were examined in the rat. A single intraperitoneal injection of caffeine induced dose- and time-dependent increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) in the cerebral cortex. The increases were significant at a caffeine dose of 25 mg/kg and greatest (+188, +388, and +71%, respectively) at a dose of 100 mg/kg in rats killed 30 min after caffeine administration. Caffeine also increased the plasma concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed in the brain, whereas the caffeine-induced increase in the plasma concentration of allopregnanolone was maximal at a dose of 50 mg/kg. Caffeine increased the plasma concentration of corticosterone, but it had no effect on the brain or plasma concentrations of 3alpha, 21-dihydroxy-5alpha-pregnan-20-one and dehydroepiandrosterone. Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not affected by caffeine in adrenalectomized-orchiectomized rats. These results suggest that neuroactive steroids may modulate the stimulant and anxiogenic effects of caffeine.

Animals↗
PubMed1997

The role of dopamine in the behavioral effects of caffeine in animals and humans.

Dopamine has been proposed to mediate some of the behavioral effects of caffeine. This review discusses cellular mechanisms of action that could explain the role of dopamine in the behavioral effects of caffeine and summarizes the results of behavioral studies in both animals and humans that provide evidence for a role of dopamine in these effects. Caffeine is a competitive antagonist at adenosine receptors and produces a range of central and physiological effects that are opposite those of adenosine. Recently, caffeine has been shown to enhance dopaminergic activity, presumably by competitive antagonism at adenosine receptors that are colocalized and interact functionally with dopamine receptors. Thus, caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity. Consistent with this interpretation, preclinical behavioral studies show that caffeine produces behavioral effects similar to classic dopaminergically mediated stimulants such as cocaine and amphetamine, including increased locomotor activity, increased turning behavior in 6-hydroxydopamine-lesioned animals, stimulant-like discriminative stimulus effects, and self-administration. Furthermore, caffeine potentiates the effects of dopamine-mediated drugs on these same behaviors, and some of caffeine's effects on these behaviors can be blocked by dopamine receptor antagonists. Although more limited in scope, human studies also show that caffeine produces subjective, discriminative stimulus and reinforcing effects that have some similarities to those produced by cocaine and amphetamine.

Animals↗
PubMed1998

Lack of NMDA receptor involvement in caffeine-induced locomotor stimulation and tolerance in rats.

The involvement of NMDA-type glutamate receptors in caffeine's locomotor stimulant effects and the development of tolerance to these effects was examined in rats. Caffeine and the noncompetitive NMDA receptor antagonists, MK-801 and phencyclidine (PCP), were examined alone and in combination. Caffeine produced a biphasic dose-effect curve. Both MK-801 and PCP increased locomotor activity at the highest doses tested. MK-801 and PCP shifted the caffeine curve upward, but only with the highest doses that increased locomotor activity when given alone. For the tolerance experiment, osmotic pumps containing either MK-801 or nothing at all and were implanted in rats that were given either caffeinated or drug-free tap water to drink. All rats drinking caffeine showed tolerance to its locomotor stimulant effects, whereas rats drinking drug-free tap water did not. Chronic infusion of MK-801 (0.1 and 0.3 mg/kg/day) failed to block the development of tolerance to caffeine. The 0.3 mg/kg/day infusion of MK-801 appeared to slightly delay the development of tolerance to caffeine, but this effect was probably due to the locomotor stimulant effects of this infused dose of MK-801 alone. These data provide no evidence that NMDA-type glutamate receptors play a crucial role in mediating caffeine's locomotor stimulant effects or tolerance to these effects.

Animals↗
PubMed1998

Caffeine has similar pharmacokinetics and behavioral effects via the i.p. and p.o. routes of administration.

Caffeine administered intraperitoneally (i.p.) or orally (p.o.) decreased the reinforcement rate and increased the nonreinforced response rate in a dose-related fashion under a differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions. These effects were similar following both routes of caffeine administration. The parallel pharmacokinetics for i.p. and p.o. caffeine were each determined and related to the respective effects of caffeine on reinforcement rate. Serum caffeine concentrations were similar across the session after the absorption phase for a given dose. Consequently, the effect remained in approximately the same range within a dose, and no single dose possessed a full concentration-effect relation for the two routes. The effects of i.p. and p.o. caffeine on reinforcement rate plateaued at doses higher than 40 mg/kg, which produced a serum caffeine concentration of approximately 25 microg/ml regardless of the route of administration. The EC50 values were 7.34 and 9.93 microg/ml for i.p. and p.o. caffeine, respectively. This study as well as our previous studies demonstrated that the i.p. route is dependable for studying caffeine dose response relations but not for studying other drugs (e.g., midazolam). The possible mechanism accounting for this difference is discussed.

Administration, Oral↗
PubMed2000

Caffeine during sleep deprivation: sleep tendency and dynamics of recovery sleep in rats.

The adenosine antagonist caffeine disrupts sleep, but whether caffeine promotes wakefulness by interfering with the expression of sleep or by attenuating sleepiness is unknown. The ability of caffeine to reduce sleep tendency in rats was directly tested by quantifying the number of stimuli needed to maintain wakefulness during sleep deprivation for 6 h after systemic caffeine treatment. In addition, the influence of caffeine on the dynamics between nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep was investigated by comparing the magnitude and time course of the compensatory sleep responses for 42 h postsleep deprivation. Caffeine significantly reduced the attempts to sleep during sleep deprivation, F(1,9) 8.83, p = 0.0157; 44.9% of vehicle), but did not change compensatory slow-wave activity during recovery sleep. During the initial recovery phase, caffeine suppressed compensatory REM sleep and reduced, but did not block, compensatory NREM sleep duration and continuity. By 42 h postsleep deprivation, the amount of NREM recovered (70.0% of deficit) did not differ from vehicle. In contrast, the REM sleep deficit recovered after caffeine (100%) was more than after vehicle (43.9%). Thus, caffeine slowed the rate of compensatory sleep after sleep deprivation, as indexed by the duration of sleep states and sleep continuity.

Animals↗
PubMed2003

Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations.

Caffeine is characterised as a central nervous system stimulant, also affecting metabolic and cardiovascular functions. A number of studies have demonstrated an effect of caffeine on the excretion of catecholamines and their metabolites. Urinary epinephrine and norepinephrine have been shown to increase after caffeine administration. Similar trends were observed in our study in adrenaline (ADR) and noradrenaline (NORADR) levels and additionally a dose dependent effect of caffeine. The effect of caffeine on cognitive performance, blood pressure, and catecholamines was tested under resting conditions and under mental workload. Each subject performed the test after oral administration of 1 cup and then 3 cups of coffee. Root mean square error (RMSE) for the tracking task was continuously monitored. Blood pressure was also recorded before and after each stage of the experiment. Catecholamines were collected and measured for three different conditions as: at rest, after mental stress alone, after one dose of caffeine under stress, and after triple dose of caffeine under stress. Comparison of the performance of each stage with the resting conditions revealed statistically significant differences between group of smokers/coffee drinkers compared with the other two groups of non-coffee drinkers/non-smokers and non-smokers/coffee drinkers. There was no statistically significant difference between the last two groups. There was an increase of urine adrenaline with 1 cup of coffee and statistically significant increase of urine noradrenaline. Both catecholamines were significantly increased with triple dose of caffeine. Mental workload increased catecholamines. There was a dose dependent effect of caffeine on catecholamines.

Adolescent↗
PubMed2000

Dose and time dependent effects of caffeine on superoxide release, cell survival and DNA fragmentation of alveolar macrophages from rat lung.

In this study, the effect of two concentration ranges of the cAMP phosphodiesterase inhibitor, caffeine, on alveolar macrophage function was investigated by measuring survival rate, superoxide anion production and DNA fragmentation. The results show caffeine induced apoptosis in alveolar macrophages in a dose dependent manner. The survival rate of the cells exposed to low concentrations of caffeine (<5 mM) increased remarkably with a peak at 2.5 mM. At this concentration, caffeine failed to affect superoxide anion production and DNA degradation. However, at higher concentrations (5-20 mM), at which the viability was higher than the control, a significant increase in both superoxide production and DNA degradation, as judged by agarose gel and diphenylamine reaction, was obtained for 3 and 24 h of culture. The effect of caffeine on survival rate was also time dependent. At low caffeine concentrations, macrophages survived with a viability of 90-97% after 3 days. At moderate concentrations, the cells maintained viability up to 24 h but at concentrations higher than 20 mM, caffeine inhibited cell survival and killed a fraction of the population. The results suggest that low concentrations of caffeine prevent apoptosis of macrophages, whereas at moderate concentrations caffeine induces apoptosis in these cells. The results are discussed in relation to the mechanism of cAMP.

Animals↗
PubMed2003

Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line.

This study was performed to investigate how caffeine modifies the cytotoxic effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to 5mM had less effect on clonogenic survival. The cell killing effect, due to paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic effect of paclitaxel not only in dose-response but also in time-response curves. Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose-dependent manner. In the cell cycle analysis, caffeine alone caused early G1 accumulation, whereas paclitaxel alone caused an early increase in G2-M and a decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed the effect of paclitaxel on cell cycle distribution, where a dose-dependent early increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle modifying agents, such as caffeine, potentially diminish the cytotoxic activity of paclitaxel, and one should be careful when combining such agents.

Adenocarcinoma↗
PubMed1997

Changes of response to caffeine in Ca(2+)-deficient medium in guinea-pig tenia coli.

1. After the washing out of the first caffeine, the second 25 mM caffeine-induced tension was about 50% of the first response in tenia coli. Cyclopiazonic acid (CPA), a specific sarcoplasmic reticulum Ca(2+)-ATPase blocker, almost inhibited the contraction to the next application of caffeine after the washing out caffeine in the presence of CPA. The peak tension to caffeine increased after the pretreatment with 10 mM K+ for 1 min. After pretreatment with K+ in the presence of 10(-7) M nifedipine (only phasic response), the tension to caffeine also increased. 2. The response to caffeine was rapidly reduced after incubation in a Ca(2+)-free medium and was abolished after 6 min of incubation. However, the response to caffeine in Ca(2+)-free medium 30 sec. after pretreatment with 10 mM K+ in normal Ca medium was larger. 3. These results suggest that, when the cell membrane is in the resting state, Ca2+ enters the cytoplasm by a leaky pathway and enters storage sites through Ca(2+)-ATPase. Furthermore, when the cell membrane is depolarized for a short period (less than 1 min), Ca2+ entry occurs, leading to refilling of the Ca2+ storage sites utilized by caffeine. The retention of Ca2+ in the storage sites in the Ca(2+)-free condition in tenia coli was less relative to the position in vascular smooth muscle.

Animals↗
PubMedDate not supplied

Caffeine--an atypical drug of dependence.

Caffeine has both positive effects that contribute to widespread consumption of caffeine-containing beverages and adverse unpleasant effects if doses are increased. Caffeine has weak reinforcing properties, but with little or no evidence for upward dose adjustment, possibly because of the adverse effects of higher doses. Withdrawal symptoms, although relatively limited with respect to severity, do occur, and may contribute to maintenance of caffeine consumption. Health hazards are small if any and caffeine use is not associated with incapacitation. Thus, although caffeine can be argued to fulfill regulatory criteria as a dependence-producing drug, the extensive use of caffeine-containing beverages poses little apparent risk to the consumer or to society. The positive stimulatory effects of caffeine appear in large measure to be due to blockade of A2A receptors that stimulate GABAergic neurons of inhibitory pathways to the dopaminergic reward system of the striatum. However, blockade of striatal A1 receptors may also play a role. The mechanisms underlying negative effects of higher doses of caffeine are as yet not well defined.

Animals↗