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PubMed1996

Caffeine clearance test: a quantitative liver function assessment in patients with liver cirrhosis.

BACKGROUND: Quantitative assessment of live function is an important work-up for patients with liver cirrhosis. The aim of the present study was to clarify the role of caffeine clearance test in the quantitative measurement of metabolizing capacity of the liver. METHODS: Twenty-eight patients with liver cirrhosis and 28 normal healthy volunteers were enrolled in this study. After an overnight fast, the first blood sample was collected at 8 a.m., immediately followed by an oral administration of 150 mg caffeine. Subsequent samples of venous blood were obtained at 8.30 a.m., 9 a.m., 11 a.m., 2 p.m. and 5 p.m. The caffeine clearance was determined using two caffeine concentrations from blood samples taken at 2 p.m. and 5 p.m., which were then measured by an enzyme multiple immunoassay technique. RESULTS: The serum caffeine clearance was significantly higher in the control group than in the patient group (1.72 +/- 1.06 vs. 0.78 +/- 0.77 ml/min/kg, p < 0.0001). Elimination half-life was significantly prolonged in the patient group (3.74 +/- 1.05 vs. 2.69 +/- 0.75 hours, p < 0.0001). The influence of cigarette smoking was also evident: higher clearance and shorter half-life of caffeine were noted in the smoking subjects. In the non-smokers, caffeine clearance was 1.30 +/- 0.90 and 0.51 +/- 0.47 ml/min/kg and half-life of caffeine was 2.89 +/- 0.78 and 4.06 +/- 0.93 hours, respectively (control vs. patient, p < 0.05). In the smokers, caffeine clearance was 2.30 +/- 0.98 and 1.13 +/- 0.96 ml/min/kg and half-life of caffeine was 2.41 +/- 0.63 vs. 3.31 +/- 1.06 hours, respectively (control vs. patient, p < 0.05). During the mean six-month period of follow-up, the mortality rate was significantly higher in those patients with caffeine clearance less than 0.5 ml/min/kg than in those with clearance more than 0.5 ml/min/kg (46.1% vs. 6.7%, p < 0.05). A significantly negative correlation between the serum caffeine clearance and the Child-Pugh's score was also demonstrated (r = -0.851, p < 0.0001). CONCLUSIONS: Serum caffeine clearance determined at two points of blood concentration is a useful method to evaluate the severity of liver disease and predict short-term survival of cirrhotic patients. It offers another choice for the quantitative measurement of liver functional reservoir.

Adult↗
PubMed1997

Role of caffeine in combined analgesic drugs from the point of view of experimental pharmacology.

The interactions of caffeine (CAS 58-08-2) with acetylsalicylic acid (CAS 50-78-2, ASA) and paracetamol (CAS 103-90-2) were investigated with regard to the analgesic, antiphlogistic, antipyretic and other properties. The inhibitory effect of paracetamol and ASA on the prostaglandin biosynthesis in a cyclooxygenase preparation from bovine brain in vitro was not affected by the addition of caffeine. Caffeine additively increases the antinociceptive effect of paracetamol with regard to the heat-induced pain in the mouse, as does aminophenazone. The antinociceptive effect of aminophenazone on the mechanically induced pain in the mouse is also additively increased by caffeine. In contrast to the effect of aminophenazone on the inflammatory pain in the rat, the effect of ASA is not increased by caffeine and that of paracetamol only negligibly. The antipyretic effect of paracetamol is additively increased by caffeine in the normothermic rat. The antipyretic effect of ASA and paracetamol on the yeast-induced pyrexia of the rat is not affected by caffeine. Caffeine additively increases the acute antiexudative effect of ASA and aminophenazone on the carageenin-induced oedema of the hind paw of the rat. The increase in locomotor activity caused by caffeine in mouse and rat is neutralised or diminished when the caffeine is given in combination with paracetamol. This effect is maintained even if the rats are pretreated with the combination of active ingredients for 3 weeks. The ulcerogenic effect of ASA in the stomach of the rat is not increased by caffeine. The protective effect of ASA against the hepatotoxic effect of paracetamol in the mouse is not influenced by the addition of caffeine. The plasma levels after the oral administration of 20 mg/caffeine/ kg and 80 mg paracetamol/kg in the rat are not significantly changed when the substances are given in combination. The toxicological advantages resulting from combining ASA and paracetamol with caffeine are discussed.

Acetaminophen↗
PubMed1997

Effects of chronic caffeine administration on respiration and schedule-controlled behavior in rhesus monkeys.

The effects of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in 12 adult rhesus monkeys. In seated subjects prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia) and to elevated levels of CO2 (3%, 4% and 5%) mixed in air (hypercapnia). Acute administration of caffeine (10.0-30.0 mg/kg i.m.) produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. However, daily administration of caffeine (10.0 mg/kg i.m.) for 8 consecutive days resulted in tolerance to its respiratory-stimulant effects that was surmountable with higher doses. Caffeine-tolerant subjects also were cross-tolerant to theophylline, an active metabolite of caffeine, and to rolipram and Ro 20-1724, selective phosphodiesterase inhibitors. When chronic administration was terminated and the acute effects of caffeine were redetermined, sensitivity returned to levels obtained before chronic administration within 9 days. Drug effects on behavior were studied in monkeys trained to respond under a fixed-interval schedule of stimulus termination. Acute administration of caffeine (1.0-30.0 mg/kg i.m.) produced significant rate-increasing effects on fixed-interval responding, but chronic administration resulted in tolerance that was insurmountable, such that no dose increased responding above control rates. Although the time course for development and loss of tolerance to the behavioral effects of caffeine corresponded closely with respiration, cross-tolerance did not extend to the behavioral effects of rolipram. Chronic caffeine administration had little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance was pharmacodynamic. The results suggest that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV phosphodiesterase plays a prominent role in caffeine-induced respiratory stimulation.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed2005

The effects of caffeine and expectancy on attention and memory.

The present study contrasted caffeine's effects on individuals who expect caffeine to stimulate them and those who do not. Secondly, whether a message that caffeine rather than placebo was administered would also affect these two groups of subjects differently was investigated. The study was conducted single-blind in a 2x2x2 mixed design. The between subjects factor was whether they expected caffeine to stimulate them (E+) or not (E-) according to their self reports obtained before the experiment began. The within subjects factors were message (told caffeine vs told placebo) and beverage type (given caffeine vs placebo). Sixteen subjects in each group (n=32) performed on signal detection, memory scanning and delayed free recall tasks following ingestion of either caffeinated or decaffeinated coffee on two sessions each, a total of four experimental sessions. On each session, subjects were given a message regarding their drink (told caffeine vs told placebo). However, on two sessions there was a mismatch between the message and drink given. For signal detection, performance under caffeine was better than placebo in the E+ but not the E- group. However, subjects in the E+ group did not benefit more than the E- group in either message condition. On memory scanning, detections and false alarms did not differ for either beverage, nor was there a differential finding in the E+ and E- groups. However, reaction time under caffeine condition was shorter. No effects of message were found. Caffeine and message also did not have any effect on performance on the delayed free recall task. The hypothesis that caffeine and message would affect E+ and E- subjects differentially was partly supported.

Adolescent↗
PubMed2005

Caffeine at work.

RATIONALE: There is a large literature on the effects of caffeine on performance. Most of the studies have been conducted in the laboratory and further information is required on the effects of caffeine consumption on performance and safety at work. OBJECTIVES: The present studies aimed to determine whether the level of caffeine consumption influenced changes in alertness and performance over the working day. Secondary analyses of a large epidemiological database were also conducted to examine associations between caffeine consumption and cognitive failures and accidents at work. METHODS: In the first study 110 volunteers, all of whom were regular caffeine consumers, rated their alertness and carried out a simple reaction time task before and after work on a Monday and Friday. Caffeine consumption during the day was recorded and volunteers were sub-divided into low and high consumers on the basis of a median split (220 mg/day). The second study involved secondary analyses of a database formed by combining the Bristol Stress and Health at Work and Cardiff Health and Safety at Work studies. In the first analyses associations between caffeine consumption and frequency of cognitive failures were examined in a sample of 1253 white-collar workers. The second set of analyses examined associations between caffeine consumption and accidents at work in a sample of 1555 workers who were especially at risk of having an accident. RESULTS: The results from the first study showed that those who consumed higher levels of caffeine reported significantly greater increases in alertness over the working day and a significantly smaller slowing of reaction time. The results from the second study demonstrated significant associations between caffeine consumption and fewer cognitive failures and accidents at work. After controlling for possible confounding factors it was found that higher caffeine consumption was associated with about half the risk of frequent/very frequent cognitive failures and a similar reduction in risk for accidents at work. CONCLUSIONS: Overall, the results from the three analyses show that caffeine consumption may have benefits for performance and safety at work.

Accidents↗
PubMed1992

Is caffeine consumption a risk factor for osteoporosis?

High caffeine consumption has been proposed as a risk factor for osteoporotic fracture, but the evidence associating high caffeine intake with low bone density is inconsistent. We therefore examined the influence of caffeine consumption on bone mineral at six skeletal sites in an age-stratified random sample of white women residing in Rochester, Minnesota. After age adjustment, there was no association between overall caffeine consumption and bone mineral at five of the six sites. In the femoral shaft, however, there was a statistically significant interaction between age and caffeine consumption so that high caffeine intake was associated with slight reductions in bone mineral among elderly subjects but with modestly increased bone mineral at younger ages. When caffeine intake was categorized by source, no consistent influence of coffee, tea, or other caffeinated beverage consumption could be detected on bone mineral. Caffeine intake was, however, positively associated with cigarette smoking and alcohol consumption. After adjusting for age, caffeine consumption was not correlated with biochemical indices of bone turnover, circulating concentrations of estradiol and estrone, or other dietary and musculoskeletal variables. These data suggest that caffeine intake in the range consumed by a representative sample of white women is not an important risk factor for osteoporosis. Among elderly women, however, in whom calcium balance performance is impaired, high caffeine intake may predispose to cortical bone loss from the proximal femur.

Adult↗
PubMed1990

Direct inhibition of chicken gizzard smooth muscle contractile apparatus by caffeine.

The mechanism of the inhibitory effect of caffeine on smooth muscle contraction was examined using chicken gizzard. Caffeine (0.1-5 mmol/l) inhibited the KCl-induced contraction of the muscle with an IC50 of 1.1 mmol/l. Forskolin (0.01-10 mumol/l) also inhibited KCl-induced contraction. The inhibitory effect of caffeine was potentiated by a low concentration of forskolin (0.3 mumol/l) and the inhibitory effect of forskolin was potentiated by a low concentration of caffeine (0.1 mmol/l). Although caffeine and forskolin increased tissue cyclic AMP levels, caffeine inhibited the KCl-induced contraction more strongly than forskolin at a given cyclic AMP level. Caffeine (1-40 mmol/l) inhibited the contractions induced by 3 mumol/l Ca2+ in Triton X-100-permeabilized muscle. Caffeine (1-40 mmol/l) inhibited the phosphorylation of 20 kDa myosin light chain (MLC) in native actomyosin preparation and the inhibition was enhanced by decreasing the ATP concentration in the reaction medium. Calmodulin (CaM) activity, as monitored by Ca2+/CaM-dependent erythrocyte membrane (Ca2+ + Mg2+)-ATPase, was not affected by 20 mmol/l caffeine. Time-dependent dephosphorylation of MLC upon removal of Ca2+, an indicator of phosphate activity, was not affected by caffeine. Caffeine also inhibited the Ca2(+)-independent contraction in thiophosphorylated permeabilized muscle. These results indicate that caffeine inhibits smooth muscle contraction by a direct inhibition of MLC kinase and actin-myosin interaction. A part of the inhibitory effect may be mediated by cyclic AMP-dependent mechanism(s).

Actomyosin↗
PubMed2000

Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity.

RATIONALE: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. OBJECTIVE: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. METHODS: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. RESULTS: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. CONCLUSION: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.

Adult↗
PubMed1985

Circulatory effects of coffee in relation to the pharmacokinetics of caffeine.

Drinking coffee results in an increase in blood pressure (BP) after an interval of caffeine abstinence. During chronic caffeine intake this pressor response disappears and adaptation to the circulatory effects of caffeine develops. This study was designed to determine whether a pressor response to coffee occurs during chronic caffeine intake if low basal plasma caffeine levels are achieved by a period of caffeine abstinence, defined by individual plasma caffeine half-life. In 8 normotensive subjects, circulatory measurements were studied after ingestion of coffee in 2 strengths, decaffeinated coffee and hot water after a caffeine abstinence of 4.5 times individual caffeine half-life. These measurements were compared to the same protocol without intervention. Coffee of both strengths resulted in a similar increase in BP (diastolic BP +/- 15%). The coffee-induced increase in forearm blood flow and plasma epinephrine levels were less pronounced. Decaffeinated coffee induced a smaller increase of diastolic BP, and after water, no changes were observed. Additionally, a negative correlation was found between the coffee-induced BP increase and basal plasma caffeine level in a group of 30 normotensive subjects (r = -0.71, p less than 0.001). During chronic caffeine intake, subjects with short plasma caffeine half-life are exposed to a pressor response after drinking coffee, despite the phenomenon of adaptation.

Adult↗
PubMed1992

Physical examination of caffeine's effects on the enamel surface of first molar in new-born rats.

Samples of the first molars of offspring whose dams were fed a diet supplemented with caffeine were examined by scanning electron microscopy, X-ray diffractometry and electron microprobe analysis. Scanning microscopy of the enamel surface of the caffeine group revealed a consistently rougher surface than in the non-caffeine controls, both before and after acid exposure. X-ray diffraction analysis of the pulverized whole tooth in the caffeine group showed broader diffraction peaks for the lattice plane reflections (202) and (300), indicating smaller crystallites. Pure enamel samples of the caffeine group examined with a Gandolfi X-ray camera also revealed more diffuse diffraction lines than in the non-caffeine controls, further indicating smaller crystallites in the enamel. The calcium and phosphorus contents of the acid-exposed samples in both control and caffeine groups were lower than the non-acid exposed control and caffeine groups by electron microprobe analysis. After exposure to acid, the calcium and phosphorus contents of the outer surface of the enamel in the caffeine group were greatly reduced as compared to that of the non-caffeine controls. Thus various methods consistently indicate that caffeine ingestion during early growth affects the enamel surface of the first molars, resulting in impaired mineralization. Caffeine intake may therefore have a negative effect on amelogenesis and possibly increases susceptibility to dental caries.

Animals↗
PubMed1983

Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine.

The development of tolerance to caffeine-induced stimulation of locomotor activity was evaluated in rats maintained chronically on average daily doses of 160 mg/kg or more of caffeine by the method of scheduled access to drinking water containing the drug. Dose-response curves were determined for caffeine (6.25-100 mg/kg) and d-amphetamine (0.39-6.4 mg/kg) during chronic drug treatment. In addition, the caffeine curve was redetermined 2-3 weeks after removal of the drug from the drinking water. A control group that had scheduled access to drug-free tap water was also tested. Caffeine produced dose-related increases in the locomotor activity of the controls but failed to modify locomotor activity of the chronic caffeine group. In contrast, d-amphetamine increased locomotor activity of both groups comparably. Spontaneous locomotor of the chronic caffeine group was reduced significantly for 4 days after drug-free tap water was substituted for the caffeine solution. The return of spontaneous locomotor activity to baseline values was associated with restored sensitivity to caffeine-induced stimulation of locomotor activity. Thus, chronic administration of caffeine to rats results in the development of tolerance to caffeine-induced stimulation of locomotor activity that is virtually complete, pharmacologically specific, and fully reversible when drug treatment is stopped. Decreases in spontaneous locomotor activity after abrupt termination of chronic caffeine administration follow a time course consistent with a drug withdrawal syndrome.

Animals↗
PubMed1987

Interactions between caffeine and adenosine agonists in producing embryo resorptions and malformations in mice.

Caffeine has previously been demonstrated to be teratogenic in mice, causing primarily limb reduction defects and cleft palate. To investigate the possibility that the mechanism of caffeine teratogenesis is related to its central stimulant activity, which is thought to result from its activity as an adenosine antagonist, the effects of the stable adenosine agonists L-phenylisopropyladenosine (L-PIA) and chloroadenosine on caffeine teratogenicity were examined. It was found that these adenosine analogs have embryolethal effects when administered intraperitoneally on Days 11 and 12 of gestation at extremely low dosages (minimal effect levels of 1 and 10 mumol/kg, respectively). Caffeine at dosages as low as 129 mumol/kg ip protected against the embryolethal effects of 5 mumol/kg L-PIA if administered simultaneously with L-PIA but not if administered 30 to 60 min after L-PIA. The maternotoxicity of either of the adenosine agonists or caffeine alone was ameliorated by coadministration of the other, particularly when the molar excess of caffeine was approximately 20-fold. These results suggest that the embryotoxicity and maternotoxicity of the adenosine agonists and the maternotoxicity of caffeine are mediated by binding to adenosine receptors. When coadministered with teratogenic dosages of caffeine (1160 to 1290 mumol/kg), L-PIA and chloroadenosine at dosage levels of 1 to 100 mumol/kg did not prevent and in some cases potentiated the teratogenic effects of caffeine. This lack of protection by L-PIA and chloroadenosine suggests that adenosine receptors are not the primary site of action for caffeine-induced teratogenicity. The embryolethal effects of L-PIA and chloroadenosine and the teratogenicity of caffeine occurred only at maternotoxic dosages. However, an analysis of the correlation structure indicates that the embryotoxicities of L-PIA and caffeine were not secondary to maternotoxicity as measured by body weight change.

2-Chloroadenosine↗
PubMed1995

Caffeine and selective visual processing.

This work addressed five issues: a) Does caffeine modulate electroencephalogram (EEG) background activity in a manner consistent with the idea of cortical "arousal"? b) Is performance in a simple speeded task improved under caffeine? c) Is visual processing more selective under caffeine? d) Does caffeine affect sensory discrimination? and e) Does it affect motor processes? We presented 16 subjects with a visual selection task under conditions of either caffeine or placebo. Background EEG data, gathered before administration of the task, revealed that caffeine resulted in lower slow-alpha power, relative to placebo, which is consistent with the idea of increased cortical "arousal." During the selection task, subjects had to respond manually to a given target conjunction of spatial frequency and orientation. Other conjunctions shared spatial frequency, orientation, or neither with the target. The four conjunctions were presented in a random sequence, with SOAs ranging between 750 and 950 ms. Event-related potentials (ERPs) to the conjunctions were recorded at standard scalp locations Fz, Cz, Pz, and Oz. Under caffeine, subjects made faster responses to target conjunctions (382.9 vs. 404.5 ms) and more hits, whereas the false-alarm rate was equal across conditions. Caffeine did not affect the selection potentials normally obtained in this task by subtracting, from ERPs to nontargets with the target spatial frequency, those to nontargets with the other frequency. However, an early differential positivity (50-160 ms) was found specifically under caffeine, indicative of increased selectivity. Difference ERPs as a function of physical parameters were not affected by caffeine, indicating no effect on sensory discrimination. Onsets of response-related lateralizations above the motor cortex were not affected by caffeine, suggesting that the shorter reaction times under caffeine were due to faster central or peripheral motor processes.

Adult↗
PubMedDate not supplied

Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data.

The teratogenic effect of caffeine has been clearly demonstrated in rodents. The sensitivity of different animals species is variable. Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats. However, when caffeine is administered in fractioned amounts during the day, 330 mg/kg/day are necessary to reach teratogenicity in rats. In rodents, the most frequently observed malformations are those of the limbs and digits, ectrodactyly, craniofacial malformations (labial and palatal clefts) and delays in ossification of limbs, jaw and sternum. Nevertheless, even in rodents, caffeine can be considered as a weak teratogenic agent, given the quite large quantities of caffeine necessary to induce malformations and the small number of animals affected. In humans, caffeine does not present any teratogenic risk. The increased risk of the most common congenital malformations entailed by moderate consumption of caffeine is very slight. However, caffeine potentiates the teratogenic effect of other substances, such as tobacco, alcohol, and acts synergistically with ergotamine and propranolol to induce materno-fetal vasoconstrictions leading to malformations induced by ischemia. Therefore, even though caffeine does not seem to be harmful to the human fetus when intake is moderate and spread out over the day, some associations, especially with alcohol, tobacco, and vasoconstrictive or anti-migraine medications should be avoided. Maternal consumption of caffeine affects brain composition, especially in case of a low-protein diet and also seems to interfere with zinc fixation in brain. Maternal exposure to caffeine induces also long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety in rat offspring, whereas in humans, more studies are needed to ascertain long-term behavioral effects of caffeine ingestion by pregnant mothers.

Abortion, Spontaneous↗
PubMed2006

Caffeine as a flavor additive in soft-drinks.

Over 60% of soft-drinks sold in the United States contain caffeine, a mildly addictive psycho-active chemical, as a flavor additive. Using sweeteners as controls, we assessed whether caffeine has flavor activity in a cola soft-drink. A forced-choice triangle discrimination methodology was used to determine detection thresholds of caffeine in sweeteners and a cola beverage. The subjects (n=30, 28 female, 23+/-4 years old) were trained tasters and completed over 1600 discrimination tests during the study. The mean detection thresholds for caffeine in the sweet solutions were: 0.333+/-0.1mM sucrose; 0.467+/-0.29 mM aspartame; 0.462+/-0.3mM sucralose, well below the concentration in common cola beverages (0.55-0.67 mM). A fixed concentration of caffeine, corresponding to the concentration of caffeine in a common cola beverage (0.67 mM) was added to the sweeteners and a non-caffeinated cola beverage. Subjects could distinguish between caffeinated and non-caffeinated sweeteners (p<0.001), but all subjects failed to distinguish between caffeinated and non-caffeinated cola beverage (p=1.0). Caffeine has no flavor activity in soft-drinks yet will induce a physiologic and psychologic desire to consume the drink.

Adult↗
PubMed2005

Cross-sensitization between caffeine- and L-dopa-induced behaviors in hemiparkinsonian mice.

Adenosine A(2A) receptor (A(2A)R) antagonists, including the non-specific adenosine antagonist caffeine, have been proposed as a novel, non-dopaminergic treatment strategy for Parkinson's disease (PD). However, the long-term interaction between caffeine and L-dopa treatment in PD models has not been characterized. We examined the interaction between caffeine and L-dopa following a repeated treatment paradigm in hemiparkinsonian mice. In contrast to the progressively sensitized rotational behavior induced by daily L-dopa (2.0 mg/kg) treatment, tolerance for the rotational response to daily caffeine (2.5 or 10 mg/kg) treatment tended to develop over several weeks. However, after a subsequent two-week washout, challenge with same drug demonstrated an extinction of the sensitized L-dopa-induced rotation, but a sensitization of the caffeine-induced rotation. In a cross-challenge paradigm, daily treatment of mice with L-dopa (compared to daily saline) produced a three-fold enhancement in the rotational response to a subsequent re-challenge with caffeine. Similarly, daily treatment of mice with caffeine produced a six-fold enhancement in the rotational response to a subsequent re-challenge with L-dopa. Furthermore, daily co-administration of caffeine plus L-dopa produced enhanced rotational behavior, compared to caffeine or L-dopa alone, indicating an additive or synergistic interaction between caffeine and L-dopa during repeated treatment. Cross-sensitization between caffeine and L-dopa following repeated treatment and their positive interaction during chronic co-adminstration in hemiparkinsonian mice suggest that repeated exposure to caffeine may alter L-dopa responses in PD.

Adenosine A2 Receptor Antagonists↗
PubMed1997

Caffeine mimics the effect of a dopamine D2/3 receptor agonist on the expression of immediate early genes in globus pallidus.

In order to evaluate the effect of caffeine on striatopallidal neurons we used in situ hybridization to examine the mRNA expression of the immediate early genes (IEGs), c-fos, fos B, c-jun, jun B, NGFI-A and NGFI-B in globus pallidus in rats given single or repeated administration of caffeine. A significant induction of c-fos mRNA, but not of any of the other IEGs, was found 2, 4 and 8 hr after a single injection of 50 mg/kg caffeine. Following repeated injections of caffeine for 2 weeks a single challenge with caffeine did not induce the expression of any of the studied genes. The ability of caffeine to increase pallidal c-fos mRNA expression was mimicked by the dopamine D2/3 receptor agonist quinpirole (1 or 3 mg/kg), whereas the dopamine D2/3 receptor antagonist raclopride (2 mg/kg) was ineffective. Caffeine and quinpirole did not have synergistic effects when given together. The caffeine-induced c-fos mRNA expression was not counteracted by concomitant treatment with raclopride. The present data provide evidence that acute treatment with caffeine reduces the activity of the striatopallidal neuron, and since this neuron is inhibitory the result is an increased activity in globus pallidus. The effect of blocking the striatal A2A receptors with caffeine is essentially identical to that observed after activation of dopamine D2 receptors, but is independent of these receptors. The fact that pallidal c-fos mRNA expression decreased upon repeated administration of caffeine may be related to the development of tolerance to locomotion stimulation that occurs following chronic caffeine ingestion.

Animals↗
PubMed1997

A systematic survey of caffeine intake in Vermont.

Detailed data were collected on lifetime caffeine intake from 202 Vermont residents using a random-digit dial telephone survey. The sample appeared representative and test-retest reliability of caffeine intake was high (r = .95). Almost all participants (96%) had ever used and most (83%) presently used one or more caffeinated beverages weekly. The average caffeine intake was 186 mg/day. Many caffeine users (61%) used caffeinated beverages other than coffee. Current caffeine intake was a poor measure of lifetime intake. For example, among ever-users of caffeine, 41% had stopped at least 1 type of caffeinated beverage and 14% had stopped caffeine altogether. Cessation was mostly due to health concerns and unpleasant side effects. It was concluded that simply asking about "usual" coffee use is a poor and biased estimate of lifetime caffeine use. Thus, prior findings that caffeine is not associated with medical or behavioral disorders may represent false-negative results.

Adolescent↗