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PubMed1999

Caffeine withdrawal: a parametric analysis of caffeine dosing conditions.

Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been only moderately well characterized in humans. Four double-blind experiments were conducted in independent groups of healthy participants to assess the conditions under which withdrawal symptoms occur upon cessation of low to moderate doses of caffeine. In experiment 1, there was no evidence that the range or magnitude of caffeine withdrawal symptoms differed when 300 mg of caffeine was consumed as a single dose in the morning versus 100 mg at three time points across the day. In experiment 2, both the range and severity of withdrawal increased as a function of caffeine maintenance dose (100, 300, and 600 mg/day), with even the lowest dose (100 mg) producing significant caffeine withdrawal. Experiment 3 showed that when individuals were maintained on 300 mg caffeine/day and tested with a range of lower doses (200, 100, 50, 25, and 0 mg/day), a substantial reduction in caffeine consumption (</=100 mg/day) was necessary for the manifestation of caffeine withdrawal. Experiment 4 manipulated duration of exposure to caffeine (1, 3, 7, or 14 days of 300 mg/day) and showed that caffeine withdrawal occurred after as little as 3 days of caffeine exposure, with a somewhat increased severity of withdrawal observed after 7 or 14 days of exposure. As a whole, this set of experiments provides the most complete parametric characterization of caffeine withdrawal to date and suggests that caffeine physical dependence can occur under more modest conditions (i.e., fewer doses per day, lower daily dose, shorter duration of exposure) than previously recognized.

Adult↗

PubMed1995

Caffeine withdrawal symptoms and self-administration following caffeine deprivation.

This study examined the effects of complete or partial caffeine deprivation on withdrawal symptomatology and self-administration of coffee in caffeine-dependent coffee drinkers. Nine habitual coffee drinkers abstained from dietary sources of caffeine for 33.5 h. Caffeine deprivation was manipulated by administering capsules containing 0%, 50%, or 100% of each subject's daily caffeine intake (complete, partial, and no deprivation conditions). Caffeine withdrawal symptomatology was measured using self-report questionnaires. Caffeine self-administration was measured using: i) the amount of coffee subjects earned on a series of concurrent random-ratio schedules that yielded coffee and money reinforcers; ii) the amount of earned coffee they consumed. Saliva samples revealed that subjects complied with the caffeine abstinence instructions. Caffeine withdrawal symptoms occurred reliably following complete caffeine deprivation, though not in the partial deprivation condition. Caffeine self-administration was not related to deprivation condition. We conclude that caffeine withdrawal symptomatology is not necessarily associated with increased caffeine consumption.

Adult↗

PubMed1986

Influence of caffeine on exercise performance in habitual caffeine users.

The effect of caffeine on the exercise responses of six women habituated to caffeine (greater than 600 mg/day) was examined during 1-h running at 75% VO2 max on a motorized treadmill. Each subject completed a placebo (PL) and a caffeine ingestion (CC) trial while maintaining normal caffeine intake. The subject then abstained from caffeine for 4 days and again ran after receiving caffeine (CW). Caffeine dosage for all trials was 5 mg/kg body weight. Ingestion of caffeine after withdrawal (CW) resulted in the greatest physiologic effects. Exercise oxygen uptake was significantly elevated by 0.17 l/min over the PL and CC trials (P less than 0.05). The CW trials resulted in an overall R value of 0.79 +/- 0.04 compared with 0.85 +/- 0.08 for the PL and 0.83 +/- 0.04 for the CC trials. Caffeine had its greatest effect on the resting free fatty acid levels after withdrawal: 1104 +/- 425 mu Eq/l compared with 543 +/- 288 for the PL and 839 +/- 526 for the CC. Postexercise lactates were similar for all trials. Post-exercise plasma norepinephrine and dopamine were the highest after the CW trials. The results suggest that habitually high caffeine users acquire a tolerance to caffeine which reduces its effects during prolonged exercise. Furthermore, to magnify the effect of caffeine, habitual users should withdraw from caffeine use for about 4 days.

Adult↗

PubMed1997

Behavioral characterization of caffeine and adenosine agonists during chronic caffeine exposure.

Many of the behavioral actions of caffeine are mediated by its blockade of adenosine receptors, a notion that may have implications for tolerance and supersensitivity associated with chronic caffeine exposure. To examine possible interactions between chronic caffeine and adenosine-related actions of several drugs, the acute effects of caffeine and three adenosine agonists on behavior maintained by a Multiple Fixed-Interval (FI), Duration > 5 s schedule of reinforcement were studied using rats chronically consuming either 0 (tap water control), 0.5 mg/ml, or 1.0 mg/ml of caffeine in their drinking water. 5'-(N-cyclopropyl)-carboxamidoadenosine [CPCA (preferential A2 agonist)], 5'-N-ethylcarboxamidoadenosine [NECA (about equal agonist activity at A1 and A2 receptors)], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA (preferential A1 agonist)], as well as caffeine (nonspecific adenosine antagonist), were administered acutely i.p. after behavior stabilized. Dose-related decreases in overall response rate were produced by all adenosine agonists. Acute administration of all adenosine agonists and higher doses of caffeine increased average lever-press durations under the FI schedule from about 0.3 s to between 1 and 3 s, a three- to 10-fold increase. CPCA and NECA were 10 times more potent than R-PIA on all measures. Caffeine increased overall response rate under the FI schedule at doses of 3-30 mg/kg in nontolerant rats, and decreased rates at higher doses, which also increased lever-press durations. Insurmountable tolerance was seen to the rate-increasing effects of caffeine on behavior under the FI schedule, in rats exposed chronically to caffeine. Modest evidence of surmountable tolerance was seen in the rate-decreasing effects on the Duration > 5 s schedule. No tolerance to increases in lever-press durations or decreases in response rates was detected. Chronic exposure to caffeine did not alter the acute effects of the adenosine agonists: on all measures and with all adenosine agonists, the dose-effect curves for the three caffeine-exposure groups were indistinguishable from one another. The relative potencies suggest that the acute actions of adenosine agonists are related to A2 receptors. This is consistent with the failure to detect supersensitivity, since upregulation associated with chronic caffeine exposure appears primarily in A1 receptors.

Adenosine↗

PubMed2002

Effect of caffeine-deprivation on liking for a non-caffeinated drink.

Liking for a novel non-caffeinated drink decreases when regular caffeine consumers are exposed repeatedly to that drink when caffeine-deprived; however, this dislike is not manifest if people are subsequently tested when not caffeine-deprived (Yeomans et al., 2000a). The present study investigated the basis for this effect, and in particular, whether the decrease in liking observed is specific to the drink flavour experienced during caffeine-deprivation. Twenty-four caffeine consumers evaluated five novel drinks (fruit teas) at pre-training. For each person, the drink with the median liking score was subsequently consumed mid-morning after 12 h caffeine-deprivation on four non-consecutive training days. Rated pleasantness of this drink decreased significantly over these four training days. Subjects subsequently re-evaluated all five drinks on a test day when half the consumers were given 100mg caffeine two hours prior to testing, with the remainder receiving placebo. The group who remained deprived continued to express depressed liking for the exposed (target) drink, compared to their pre-training rating of that drink. In contrast, rated pleasantness was not depressed compared to pre-training ratings in the group who had received caffeine prior to testing. Rated pleasantness of the four unexposed drinks was equivalent to pre-training ratings, for both groups, suggesting that the effect of exposure on ratings of the target drink was specific to that drink. As expected, there was some evidence of improved mood in the group receiving caffeine on the test day; but as it was only ratings of the target drink that differed across groups, the group difference cannot be attributed to general effects of mood on use of the rating scale. These data suggest that the reversal of acquired changes in liking for drinks when consumers are changed from a caffeine-deprived to an undeprived condition is best explained in terms of state-dependent learning, that is specific to the drink experienced during caffeine-deprivation.

Adult↗

PubMed1993

Duration of caffeine abstention influences the acute blood pressure responses to caffeine in elderly normotensives.

The effect of an acute oral caffeine load (250 mg capsule) and matching placebo on blood pressure and pulse rate were studied after 48 h caffeine abstention in 8 elderly, normotensive regular caffeine users. The caffeine loading phase was repeated after only 12 h abstention. Following 48 h abstention, supine systolic and diastolic blood pressure were higher for the 120 min study period after the acute caffeine load than placebo (12.1 mm Hg, 95% C.I. 4.3-19.9 mm Hg; P = 0.008 and 7.4 mm Hg, 3.6-11.2 mm Hg; P < 0.001 respectively). Similar differences were seen in standing blood pressure, though pulse rate was unchanged throughout. The pressor response to the acute caffeine load was significantly greater after a 48 h than a 12 hour caffeine abstention period, for supine and standing systolic and diastolic blood pressure. The changes in plasma caffeine levels after acute loading were similar after the 2 different abstention periods. Caffeine ingestion after 48 h abstention has an acute pressor effect in normotensive elderly subjects which is abolished if the abstention period is reduced to 12 h. Acute caffeine ingestion is unlikely to have a significant pressor effect in elderly normotensive subjects who are regular caffeine users as the normal period of caffeine abstention (i.e. overnight) is too short to abolish tolerance.

Administration, Oral↗

PubMed2005

Association of serum caffeine concentrations with blood lipids in caffeine-drug users and nonusers - results of German National Health Surveys from 1984 to 1999.

Previous studies regarding effects of caffeine on lipids focused mainly on coffee consumption, the real association of serum caffeine concentrations with blood lipids is unclear. 814 caffeine-drug users who had taken any caffeine/caffeine-containing pharmaceutical products and 623 nonusers without any drug use in the last seven days before the medical interview were identified from German National Health Surveys from 1984 to 1999. Serum caffeine concentrations were measured by using EIA for caffeine-drug users and nonusers in the same laboratory. Blood lipids were measured routinely for all survey participants. The association of caffeine concentrations with blood lipids was established by means of partial correlation analysis and regression analysis. After controlling for influence factors, caffeine concentrations were closely positively related to triglycerides in caffeine-drug users (male: r = 0.245, p < 0.001; female: r = 0.117, p = 0.018) and related to HDL-C in female nonusers (r = 0.245, p < 0.001). No associations were found between caffeine concentrations and total cholesterol and LDL-C levels in any groups of our study. Acute intake of caffeine might increase triglycerides levels especially in men while chronic intake of caffeine might be weakly but positively associated with HDL-C concentrations in women. The effects of caffeine on the pathogenesis of cardiovascular diseases should be further confirmed through epidemiological studies.

Adolescent↗

PubMed1998

Serum caffeine and paraxanthine as markers for reported caffeine intake in pregnancy.

PURPOSE: Previous studies of maternal caffeine use and pregnancy outcome have relied on self-reported use. Even if these were perfectly accurate, inter-individual differences in caffeine metabolism result in a relatively weak correlation between caffeine intake and serum concentration. The purpose of this study was to determine whether the serum concentration of caffeine or its primary metabolite, paraxanthine, obtained at an unknown time during working hours, is useful to distinguish between pregnant women who report consuming small and large amounts of caffeine. METHODS: We selected from the Birmingham fetal growth study 60 women with normal pregnancy outcomes who reported consuming < or = 0.8 mg/kg/day of caffeine in a 24-hour dietary recall, 60 who consumed 0.81-2.5 mg/kg/day, 60 who consumed 2.51-5.0 mg/kg/day and 59 who consumed > or = 5.01 mg/kg/day. These women had serum drawn for storage during regular clinic hours on the same day as the recall interview. Caffeine and paraxanthine were measured in the stored serum using high performance liquid chromatography. RESULTS: The weighted kappa coefficient between strata of caffeine intake and quartiles of serum paraxanthine was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and 0.51, respectively, for quartiles of serum caffeine. The Pearson correlation coefficient between intake and paraxanthine was 0.50 for smokers and 0.53 for nonsmokers, and 0.37 and 0.51, respectively, for serum caffeine. These values are comparable to the correlation between reported smoking and serum cotinine in pregnancy. CONCLUSIONS: The serum concentrations of paraxanthine, and to a lesser degree, caffeine are useful to distinguish between women with varying levels of caffeine intake.

Biomarkers↗

PubMed1999

Biosynthesis and catabolism of caffeine in low-caffeine-containing species of Coffea.

Leaves of Coffea salvatrix, Coffea eugenioides, and C. bengalensis contain approximately 3-7-fold lower levels of caffeine than those of Coffea arabica. There was more extensive biosynthesis of caffeine from [8-(14)C]adenine in young leaves of C. arabica than in C. salvatrix, C. eugenioides, and C. bengalensis. Degradation of [8-(14)C]caffeine, which is negligible in leaves of C. arabica, was also very slow in C.salvatrix and C. bengalensis. In contrast, [8-(14)C]caffeine was catabolized rapidly by young and mature leaves of C. eugenioides primarily by a caffeine --> theophylline --> 3-methylxanthine --> xanthine --> uric acid --> allantoin --> allantoic acid --> urea --> CO(2) + NH(3) pathway. These results indicate that the low caffeine accumulation in C. salvatrix, C. eugenioides, and C. bengalensis is a consequence of a slow rate of caffeine biosynthesis, whereas rapid degradation of caffeine also contributes to the low endogenous caffeine pool in C. eugenioides. The genes that regulate caffeine accumulation appear to be those encoding N-methyltransferase and caffeine (7-N) demethylase activities. The diversity of caffeine catabolism observed in C. arabica, C. salvatrix, C. eugenioides, and C. bengalensis, other species of Coffea, and Camellia sinensis is discussed.

Adenine↗

PubMed2005

Caffeine deprivation state modulates coffee consumption but not attentional bias for caffeine-related stimuli.

Previous research has shown that caffeine deprivation state can exert a strong influence on the ability of caffeine to reinforce behaviour. Recent work has also found evidence for an attentional bias in habitual caffeine users. It remains unclear whether deprivation state can influence attentional bias. Here we explored the relationship between caffeine deprivation, attentional bias to caffeine-related stimuli and subsequent caffeine reinforcement measured by consumption of coffee. In three experiments, participants (between-subjects: n=28; within-subjects: n=20, within-subjects: n=20) were preloaded with either caffeine (experiments 1 and 3 : 100 mg; experiment 2 : 150 mg) or placebo, and in experiments 1 and 2 they completed a novel attentional bias task involving pre-attentive word recognition, and in experiment 3 a dot-probe task. In experiments 2 and 3, this was followed by a test of coffee consumption. Greater recognition for caffeine-related words (experiments 1 and 2) and faster reaction times to probes replacing caffeine-related rather than control stimuli (experiment 3) confirmed caffeine-related attentional biases, but in no case was this affected by manipulation of caffeine-deprivation state. Participants in a deprived versus nondeprived state, however, experienced increases in drowsiness and headaches (experiment 2) and reduced alertness (experiment 3). Further, coffee consumption was greatest when participants were caffeine-deprived than when they were nondeprived. Findings are discussed in relation to prevailing theories of drug addiction.

Adolescent↗

PubMedDate not supplied

Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels.

OBJECTIVE: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake. METHODS: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM. RESULTS: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period. CONCLUSION: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis.

Adult↗

PubMed1996

Anticonvulsant activity of phenobarbital and valproate against maximal electroshock in mice during chronic treatment with caffeine and caffeine discontinuation.

We evaluated the protective activity (expressed as ED50 values in mg/kg of phenobarbital (PB, 120 min before testing) and valproate (30 min) alone or combined with caffeine in male mice with seizures induced by maximal electroshock (MES). Both antiepileptic drugs (AEDs) were administered by intraperitoneal (i.p.) injection in a single dose to mice receiving intraperitoneal caffeine either in a single dose 30 min before the test or as pretreatment every 12 h for 3 and 14 days. In addition, we determined the ED50 values of the AEDs 24 and 72 h after 14-day treatment with caffeine. Finally, we studied the influence of a challenge dose of caffeine, injected in mice 24 and 72 h after 14 days of treatment with caffeine, on the protective activity of PB or VPA. Caffeine in a single dose of 23.1 mg/kg reduced the anticonvulsant effect of PB. Its protective activity was further impaired after 3 and 14 days of caffeine treatment. The ED50 for VPA was significantly increased both by the single dose of caffeine and by chronic treatment. The anticonvulsant activity of PB and VPA measured 24 and 72 h after 14-day treatment with caffeine did not differ from control values, but a challenge dose of caffeine injected 24 or 72 h after daily injections for 14 days resulted in a significant reduction in the protective activity of both AEDs. Measurement of the total plasma levels of caffeine, VPA, and PB did not suggest pharmacokinetic interactions as an explanation for our results. Our results indicate that chronic caffeine exposure may progressively reduce the antiepileptic potency of VPA and PB.

Animals↗

PubMed2000

Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose.

Caffeine is a common psychoactive constituent of coffee, carbonated beverages, and over-the-counter medications. This study examined the effects of chronic caffeine exposure on the behavioral response to acute administrations of psychostimulant drugs on ambulatory activity and on the pharmacological characteristics of nicotine discrimination in rats. Rats were maintained continuously on caffeine added to the drinking water at a concentration of 0.25 or 1. 0 mg/ml that resulted in plasma caffeine concentrations ranging from 0.37 to 5.95 microg/ml. Rats maintained on tap water served as control groups. Exposure to the lower caffeine concentration (0.25 mg/ml) potentiated stimulatory effects of nicotine, amphetamine, and cocaine on ambulatory activity and failed to produce tolerance to the acute stimulatory effects of caffeine. In contrast, exposure to the higher caffeine concentration (1.0 mg/ml) did not alter the effects of the psychomotor stimulants on ambulatory behaviors but resulted in the development of complete, insurmountable tolerance to the acute stimulatory effects of caffeine. In the nicotine discrimination paradigm (0.4 mg/kg, training dose, a fixed-ratio 10 schedule of food delivery in a two-lever choice paradigm), rats exposed to the lower, but not to the higher, caffeine concentration acquired the nicotine discrimination significantly faster and were more sensitive to the effects of amphetamine and cocaine in substitution tests than water-drinking rats. Caffeine exposure did not change pharmacokinetic properties of nicotine (i.e., plasma levels, metabolism). In summary, exposure to two different caffeine solutions within a range of plasma levels observed in humans resulted in quantitatively distinct changes in psychostimulant-induced nonoperant and operant measures of behavior. These results suggest that dietary consumption of moderate doses of caffeine may be associated with enhanced reactions to some psychostimulants.

Amphetamine↗

PubMed2006

Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users.

RATIONALE: Caffeine produces mild psychostimulant effects that are thought to underlie its widespread use. However, the direct effects of caffeine are difficult to evaluate in regular users of caffeine because of tolerance and withdrawal. Indeed, some researchers hypothesize that the psychostimulant effects of caffeine are due largely to the reversal of withdrawal and question whether there are direct effects of caffeine consumption upon mood, alertness, or mental performance in nondependent individuals. OBJECTIVE: This study investigated the physiological, subjective, and behavioral effects of 0, 50, 150, and 450 mg caffeine in 102 light, nondependent caffeine users. METHODS: Using a within-subjects design, subjects participated in four experimental sessions, in which they received each of the four drug conditions in random order under double blind conditions. Participants completed subjective effects questionnaires and vital signs were measured before and at repeated time points after drug administration. Forty minutes after the capsules were ingested, subjects completed behavioral tasks that included tests of sustained attention, short-term memory, psychomotor performance, and behavioral inhibition. RESULTS: Caffeine significantly increased blood pressure, and produced feelings of arousal, positive mood, and high. Caffeine increased the number of hits and decreased reaction times in a vigilance task, but impaired performance on a memory task. CONCLUSION: We confirm that acute doses of caffeine, at levels typically found in a cup of coffee, produce stimulant-like subjective effects and enhance performance in light, nondependent caffeine users. These findings support the idea that the drug has psychoactive effects even in the absence of withdrawal.

Adolescent↗

PubMed2001

An evaluation of a caffeinated taurine drink on mood, memory and information processing in healthy volunteers without caffeine abstinence.

RATIONALE: Caffeine is present in a wide variety of beverages, often together with a number of other ingredients, such as sugars, taurine, glucuronolactone and vitamins. However, the majority of psychopharmacological studies have used pure caffeine tablets or drinks with doses in excess of those normally consumed in daily life. In addition, all the participants are usually deprived of caffeine for 10 h or more before the study. Consequently, it has been argued that any improvement in performance is only due to a reversal of caffeine withdrawal. OBJECTIVE: The present two studies tested participants who had minimal deprivation from caffeine (an hour or less) with an 80-mg caffeinated (80 mg/250 ml), taurine-containing beverage (commercially available) verum, which also contained sugars, glucuronolactone and vitamins. The placebos in the two studies were a sugar-free and a sugar-containing drink, in order to examine the effects of the sugar. METHODS: In total, 42 participants were tested with a rapid visual information test, a verbal reasoning test, a verbal and non-verbal memory test and a set of mood measures. Prior to testing, they were allowed ad libitum caffeinated beverages until 1 h before testing (study 1) and unrestricted caffeine use before testing (study 2). RESULTS: In both studies, the caffeinated, taurine-containing beverage produced improved attention and verbal reasoning, in comparison with a sugar-free and the sugar-containing drinks. The improvement with the verum drink was manifested in terms of both the mean number correct and the reaction times. Another important finding was the reduction in the variability of attentional performance between participants. No effects on memory were found. There were no differences in performance between the glucose and sugar-free drinks. CONCLUSIONS: Moderate doses of caffeine and taurine can improve information processing in individuals who could not have been in caffeine withdrawal.

Adolescent↗

PubMed1983

Age and prior caffeine use alter the cardiovascular and adrenomedullary responses to oral caffeine.

The effects of age and chronic caffeine use (approximately 300 mg/day) on the cardiovascular and humoral responses to 250 mg of oral caffeine (the equivalent of 2 to 3 cups of coffee) were examined. Older subjects had greater increases in blood pressure than younger subjects (p less than 0.03), and caffeine nonusers had greater blood pressure increases than caffeine users, regardless of age (p less than 0.05). Caffeine increased the product of systolic blood pressure and heart rate (an estimate of myocardial oxygen demand) in older caffeine nonusers, but this effect was absent in older caffeine users (p less than 0.01). Cardiovascular effects of caffeine could not be related temporally to changes in plasma epinephrine, which were greater in caffeine nonusers and younger subjects, or to plasma norepinephrine, renin activity or vasopressin, which did not change. Thus, age accentuates and moderate prior caffeine use attenuates the cardiovascular effects of oral caffeine; these effects are not mediated solely through the sympathoadrenal system.

Adrenal Medulla↗

PubMed1995

Mood and performance effects of caffeine in relation to acute and chronic caffeine deprivation.

The mood and performance effects of caffeine deprivation (either 90 min, overnight, or at least 7 days) and ingestion (70 and 250 mg) were compared in young adults who were normally either moderate consumers (n = 49) or nonconsumers of caffeine (n = 18). Overnight caffeine deprivation produced dysphoric symptoms characteristic of caffeine withdrawal that were reduced, but still present, after longer-term abstinence. Acute caffeine intake affected the withdrawn consumers, nonwithdrawn consumers, and nonconsumers similarly. It increased jitteriness and decrease tiredness and headache. Furthermore, hand steadiness decreased as caffeine dose increased, whereas 70 mg, but not 250 mg, of caffeine was found to enhance performance on a simple reaction time task. These findings support the view that the negative effects experienced after overnight and longer-term caffeine deprivation play a significant role in influencing consumption of caffeine-containing drinks. Therefore, it would appear that to avoid the dysphoric symptoms resulting from both under- and overconsumption, regular caffeine consumers would have to regulate their caffeine intake fairly precisely.

Acute Disease↗

PubMed2002

Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats.

The effects of caffeine on extracellular dopamine and acetylcholine have been studied in freely moving rats implanted with concentric microdialysis probes in the nucleus accumbens shell and core and in the medial prefrontal cortex. Intravenous administration of caffeine (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently increased dopamine and acetylcholine dialysate concentrations in the medial prefrontal cortex, while it did not affect dialysate dopamine in the shell and core of the nucleus accumbens. Intraperitoneal administration of caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the shell and core of the nucleus accumbens. Such effects were duplicated by intravenous administration of DPCPX, a selective antagonist of adenosine A1 receptors, and of SCH 58261, an antagonist of A2a receptors. The effect of caffeine on prefrontal dopamine and acetylcholine transmission was also studied in rats chronically administered with caffeine (25 mg/kg, twice a day for seven days). At the end of this treatment rats became tolerant to the locomotor stimulating effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these doses, however, still increased dialysate acetylcholine but did not affect dopamine in the prefrontal cortex. Therefore, in rats made tolerant to the locomotor stimulant effects of caffeine, tolerance developed to the dopamine stimulant but not to the acetylcholine stimulant effect of caffeine in the prefrontal cortex. The lack of acute stimulation of dopamine release in the nucleus accumbens shell by caffeine is relevant to the issue of its addictive properties and of the role of DA in drug- and substance-addiction. On the other hand, the dissociation between tolerance to the locomotor effects of caffeine and stimulation of acetylcholine release in the prefrontal cortex suggests that this effect might be correlated to the arousing effects of caffeine as distinct from its locomotor stimulant properties.

Acetylcholine↗