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Psychopharmacology (2010) 211:245–257DOI 10.1007/s00213-010-1900-1 Genetics of caffeine consumption and responses to caffeine Amy Yang & Abraham A. Palmer & Harriet de Wit Received: 25 March 2010 / Accepted: 25 May 2010 / Published online: 9 June 2010 associated with risk of myocardial infarction in caffeine Rationale Caffeine is widely consumed in foods and bev- erages and is also used for a variety of medical purposes.
Conclusion Modeling based on twin studies reveals that Despite its widespread use, relatively little is understood genetics plays a role in individual variability in caffeine regarding how genetics affects consumption, acute re- consumption and in the direct effects of caffeine. Both sponse, or the long-term effects of caffeine.
pharmacodynamic and pharmacokinetic polymorphisms Objective This paper reviews the literature on the genetics have been linked to variation in response to caffeine. These of caffeine from the following: (1) twin studies comparing studies may help guide future research in the role of heritability of consumption and of caffeine-related traits, genetics in modulating the acute and chronic effects of including withdrawal symptoms, caffeine-induced insom- nia, and anxiety, (2) association studies linking geneticpolymorphisms of metabolic enzymes and target receptors Keywords Caffeine . Adenosine . Dopamine .
to variations in caffeine response, and (3) case-control and prospective studies examining relationship between poly- morphisms associated with variations in caffeine responseto risks of Parkinson’s and cardiovascular diseases inhabitual caffeine consumers.
Results Twin studies find the heritability of caffeine-relatedtraits to range between 0.36 and 0.58. Analysis of poly- Caffeine is the most commonly consumed psychoactive substance use shows that predisposition to caffeine use is substance in the world. Nearly 90% of US adults consume highly specific to caffeine itself and shares little common caffeine in forms of coffee, tea, or other caffeinated food disposition to use of other substances. Genome association products (Frary et al. Caffeine’s popularity world- studies link variations in adenosine and dopamine receptors wide can be attributed to its ability to promote wakefulness, to caffeine-induced anxiety and sleep disturbances. Poly- enhance mood and cognition, and produce stimulatory morphism in the metabolic enzyme cytochrome P-450 is effects (Haskell et al. ; Lieberman et al. ). It isused clinically to treat premature neonatal apnea and as ananalgesic adjuvant (Migliardi et al. Schmidt et al.
). Caffeine causes diuresis, bronchodilatation, and a Department of Psychiatry & Behavioral Neuroscience, rise in systolic blood pressure in nonhabitualized subjects (Benowitz Mosqueda-Garcia et al. ). At low 5841 S. Maryland Ave, MC 3077,Chicago, IL 60637, USA doses, its psychological effects include mild euphoria, alertness, and enhanced cognitive performance (Liebermanet al. but at higher doses, it produces nausea, anxiety, trembling, and jitteriness (Daly and Fredholm Department of Human Genetics, The University of Chicago,Chicago, IL, USA ). Tolerance to its acute effects develops rapidly (Evans and Griffiths Robertson et al. such that of genetics to consumption of caffeine and its effects.
the effects of caffeine in habitual consumers are quite Second, we will review studies that have identified different from caffeine-naïve individuals. Physical depen- pharmacokinetic and pharmacodynamic variations that dence can develop, and withdrawal symptoms occur upon affect acute response. Third, we will discuss evidences that discontinuation of regular caffeine use (Griffiths and genetic factors influence long-term effects of caffeine.
Woodson The effects of chronic consumption are Finally, we will discuss the clinical significance and less clear. Long-term use of caffeine has been associated possible future research directions.
with an increased risk of cardiovascular diseases (Hartley etal. ; Klatsky et al. but a decreased risk inneurodegenerative disorders (Ascherio et al. Maia There are pronounced individual differences in response to caffeine. For example, some individuals are susceptibleto its anxiogenic effects (Silverman and Griffiths ) and Twin studies provide powerful evidence for the heritability others to caffeine-induced sleep disturbances and insomnia of traits including response to caffeine. Heritability refers to (Bchir et al. ). Caffeine can aggravate anxiety and degree of genetic influence and can vary from 0 (not precipitate panic attacks in patients with anxiety and panic heritable) to 1 (completely inherited). Twin studies estimate disorder, which often results in decreased consumption in heritability by comparing monozygotic twins, who share these individuals (Bruce et al. ; Charney et al. the common familial environment and the same genes, to Lee et al. Nardi et al. Individual differences in dizygotic twins, who also share common familial environ- responses to caffeine may occur at the metabolic (pharma- ment but only half of the genetic material. The contribution cokinetic) or at the drug-receptor level (pharmacodynamic), of different sources of variation to an observable trait can and they can contribute to the quality and magnitude of then be derived using biometric modeling, which attributes direct drug effects as well as to consumption of the drug.
the observed variations to genetic, common environmental, Likewise, certain individuals may be more vulnerable to the and unique environmental sources (for detailed description long-term negative health effects of caffeine. For example, of modeling techniques used in twin studies, see Kendler while the pressor effects of caffeine attenuate rapidly in ; Neale and Cardon In addition to calculating most consumers upon repeated intake, tolerance remains the heritability of traits related to caffeine sensitivity and incomplete in certain subjects (Farag et al. ; Lovallo et use, models can account for the influence of age, al. Hypertensive subjects have been shown to be environmental factors, and gender differences on response more likely to experience rise in blood pressure after and consumption patterns. Table summarizes twin studies caffeine consumption even with repeated administration investigating caffeine-related traits. Broadly, two types of (Nurminen et al. It is likely that several factors outcomes are assessed in these studies: consumption level contribute to individual differences in responses to caffeine, and direct effects such as toxicity, tolerance, withdrawal, including demographic and environmental factors such as and caffeine-induced sleep disorders. These studies find age, other drug use, circadian factors, and sleep hygiene.
heritability of caffeine traits from tea or coffee consumption One important source of variability that has received some to vary from 0.30 to 0.60 in different populations. They attention in recent years is genetic predisposition.
confirm the possibilities of caffeine consumption inheri- There is growing evidence that individual differences in tance in twins without identifying the individual genes caffeine response or caffeine consumption are related to responsible for such differential inheritance pattern. This genetic factors. Genetic factors may influence responses section will review studies that investigate the impact of to caffeine directly, by altering acute or chronic reactions genetics on consumption levels, direct effects, and the to the drug, or indirectly, by affecting other psychological specificity of these inherited traits to caffeine.
or physiological processes that are related to the drug effect, Several twin studies have shown significant contribution such as sensitivity to anxiety, rewarding, and reinforcing from genetic sources in determining caffeine intake. One effects of substances in general, or related personality traits.
such study assessed the level of caffeine consumption in Finally, genes can also alter the body’s adaptive responses to female twins using average daily consumption of coffee, long-term caffeine use. The biological mechanisms of these caffeinated tea, and caffeinated soda via individual inter- possible sources of variation likely involve interactions at views (Kendler and Prescott ). Using biometric model fitting, overall caffeine consumption was found to have a In the three sections of this paper, we will review genetic heritability of 0.43. Heavy consumption, defined as studies associated with variations in caffeine effects. First, >625 mg of caffeine daily, had a heritability of 0.77. Two we will consider twin studies that examine the contributions twin studies of male veterans examined coffee consumption Table 1 Twin studies on heritability of caffeine-related traits (sum of symptoms of tolerance andwithdrawal during maximum)during period of maximumcaffeine intake Heritability is calculated by partitioning sources of variation into genetic and common factors using twin modeling. Common factor refers toheritability that is shared across substances. Further details are provided in text and can be found in the individual papers using cups of coffee per day as outcome measure and found ated drinks over the years as recalled by the subjects. By heritabilities of 0.36–0.38 (Carmelli et al. ; Swan et al.
decomposing the variation source into additive genetic, ). These values lay in range with the results from familial environmental, and unique environmental factors studies on other twin populations using similar modeling and tracing the caffeine intake between the ages of 9 and 41, techniques, with results ranging from 0.38 to 0.58 (Hettema the best-fit model showed that family environment accounts et al. Laitala et al. Luciano et al. ; Vink et for most of the variance in caffeine use from 9 to 14 years of age, but declined afterward and from late adolescence until Genetic contribution to caffeine consumption changes middle adulthood genetic contribution accounted for 0.30– through different stages in life. A retrospective study eval- 0.45 of the variance (Kendler et al. ).
uating the use of caffeine in males from early adolescence It appeared, therefore, that genetic contribution became through middle adulthood examined the number of caffein- more pronounced throughout adolescence and then stabi- lized during adulthood. Similarly, a study of coffee joint use factor and a substance-specific factor (Kendler et consumption in Finnish twins found that coffee consump- al. ). Using this technique, Kendler and Prescott tion was affected by a set of genetic factors that was stable found that heritability for caffeine use was not over time in adults (Laitala et al. ). Self-reported correlated to heritability for alcohol, nicotine, and illicit questionnaire was used to ascertain subjects’ coffee drug use. However, other studies found that the heritability consumption in 1975 and again in 1981. There was a for coffee use overlapped with that of nicotine and alcohol, moderate correlation for consumption between the two time though 0.72 of the total heritability was specific to caffeine, points (0.58 in men and 0.55 in women), while the genetic which was considerably higher than that for nicotine and factors affecting coffee consumption remained stable at alcohol (Hettema et al. Swan et al. ). Another study assessed inherited specificity for dependence and Another process by which genetics can influence abuse liability to cannabis, cocaine, alcohol, nicotine, and caffeine response is by predisposing individuals to certain caffeine lifetime in twin pairs (Kendler et al. Scores positive or negative effects, such as susceptibility to its were calculated by summing total symptoms for abuse and withdrawal symptoms or its effects on sleep. Kendler and dependence using the DSM-IV criteria for alcohol, cocaine, Prescott (examined the extent to which genetics and cannabis; the Fagerström Test for Nicotine Dependence influence individual sensitivity to caffeine toxicity, toler- for nicotine; and the sum of symptoms of tolerance and ance, and withdrawal in female twins. Outcome measures withdrawal as the measure for caffeine dependence.
were assessed via individual interviews asking for history Tolerance for caffeine was defined as the need to use more of jitteriness, need for increased dosage, and withdrawal to obtain the same effect or diminished effect with the same symptoms per DSM-IV criteria. Using the same modeling amount. Multivariate modeling was employed to determine method as described above, the heritability for toxicity, the degree which environmental and genetic influence was tolerance, and withdrawal was estimated to be 0.45, 0.40, shared across substances. Analyzing patterns of caffeine and 0.35, respectively. A study in Australian twins tolerance and withdrawal in conjunction with that for other investigated the inheritance of caffeine-attributed sleep substances showed that genetic heritability toward caffeine disturbances and its relation to other types of sleep dependence did not correlate with heritability for depen- disturbances (Luciano et al. To test the degree of dence or abuse of illicit substances such as heroin and overlap between coffee-attributed insomnia and other types cocaine (Kendler et al. ). Instead, the best-fit model of insomnia, the study applied multivariate analysis with composed of the genetic heritability from two attributes, Cholesky decomposition to account for environmental and one for licit and one for illicit substances. Genetic liability genetic variances. On average, women reported slightly toward caffeine tolerance and withdrawal came mainly higher level of caffeine-induced insomnia and greater sleep from the licit factor, receiving little contribution from the disturbances in general than men. The overall heritability of illicit substance factor, and was highly specific to caffeine.
coffee-attributed insomnia was found to be 0.40, with three The symptoms of caffeine tolerance and withdrawal were quarters of the genetic variance unrelated to the general similar for males and females, both a heritability of 0.34.
sleep factor. Furthermore, the likelihood polychoric pheno- While these studies reached slightly different conclusions typic correlations between coffee-attributed insomnia to about the joint heritability for coffee, smoking, and alcohol other types of insomnia ranged only from 0.23 to 0.39.
use, all of them found the genetic contribution to caffeine These values were lower than the intercorrelation values and coffee consumption to be highly substance specific, among noncoffee sleep disturbances, which ranged from indicating that the mechanisms predisposed individuals in a 0.40 to 0.79. Together, these results suggested that genetic mechanisms for caffeine-attributed sleep disturbance differ Among studies of dietary sources of caffeine, the from those for other types of sleep disturbances.
measure used for assessing daily caffeine intake is One fundamental question arising from genetic studies is important. Preference for certain sources can have social whether the inherited factor predisposes an individual or cultural bases, which can confound the genetic effects.
specifically to caffeine, or if it underlies a broader Most of the studies used coffee alone or a combination of disposition to substance use in general. Epidemiological tea or coffee as dietary intake measure of caffeine, though studies indicate that smokers drink more coffee than some studies have attempted to distinguish coffee and tea nonsmokers (Swanson et al. but it is not clear drinking. In one study, daily coffee and tea drinking was whether these associations are related to genetic factors or compared in Australian twins, and a preference score for tea to drug interactions, social conditioning, or other variables.
or coffee was calculated. Heritability was estimated to be One approach to solving this question is to correlate the use 0.51 for coffee consumption and 0.26 for tea consumption of caffeine to other drugs and using the common pathway (Luciano et al. ). The analyses revealed several model and mapping the genetic contribution to a common underlying differences in patterns of coffee and tea consumption. Unlike models for coffee and caffeine be drawn. First, heavy consumers seem to differ from consumption, whose best-fit models consist of genetic and moderate and light-caffeine users on several accounts.
unique environmental factors with no contribution from Heavier caffeine users appear to be more influenced by common environment, tea consumption had a modest genetics than lighter caffeine users. This is supported by the common environment contribution. The lower heritability study by Kendler and Prescott (and by the two for tea drinking could be due to the lower caffeine content studies by Swan et al. , who reported that of tea or could signify different populations of tea versus genetic variance accounted for 0.36 in overall coffee coffee drinkers. However, there was no correlation between consumption but 0.51 for heavy consumption. Second, coffee preferences and the number of caffeinated drinks heavy use of caffeine appears to correlate more closely to consumed per day, even though tea averages lower caffeine use of other substances. Multivariate modeling to estimate content per cup than coffee. The data suggested therefore covariance between tobacco, alcohol, and coffee use that environment plays a larger role in tea than coffee calculated the common factor heritability to be 0.41 for consumption and that social environment affects tea and heavy users versus 0.28 in all users (Swan et al. coffee drinking patterns differently.
). Third, although patterns of coffee and tea consump- Certain food preferences are heritable, and this appears tion differ in ways beyond the differences in caffeine to be especially true of foods such as coffee that have content, some studies have equated caffeine intake to coffee strong tastes. A food preference study in UK twins used intake. This may introduce confounds because tea drinking principle component analysis to show that preference for is more common in certain populations.
coffee had a heritability of 0.41 while preference for tea had Taken together, the twin studies show that genetics plays a heritability of 0.36 (Teucher et al. ). A Dutch twin a significant role in individual level of caffeine consump- study of coffee preference over tea was shown to have a tion. Twin studies, while providing valuable insight on the heritability of 0.62 (Vink et al. ). One reason for interplay between environment and genetic influence on preference for coffee in an individual may be due to taste consumption, do not provide information on the molecular preference. Caffeine itself can taste bitter to certain or physiological mechanisms at work. Genetic association individuals. Taste preference testing in Australian adoles- studies have been used to identify specific genes that are cent and young adult twins showed that perceived bitterness responsible for the heritable components of these caffeine- of caffeine had a broad range heritability of 0.30 after related traits. We will briefly review the metabolism and adjusting for age, gender, and other covariates (Hansen et clinical pharmacology of caffeine as a means of introducing al. ). However, this bitterness can be masked by the genes that have been examined in association studies.
preparation methods, such as adding sugar.
These studies highlight one of the limitations in using dietary intake to estimate individual preference for caffeinein a population study, which is that factors such as Caffeine and its metabolites belong to the methylxanthine individual taste preference and social settings can influence class, which are structurally similar to cyclic nucleotides, intake, and there may be a need to account for coffee and and interact with cyclic nucleotide phosphodiesterases tea separately when studying caffeine intake. Other limi- (Arnaud Daly and Fredholm ; Fredholm et al.
tations include reliance on participant returns of surveys, ). Caffeine is absorbed rapidly and completely from using self-report of caffeine use and caffeine-related the gastrointestinal tract (Arnaud ). It is metabolized symptoms, imprecise methods of estimating dietary caf- by cytochrome P-450 enzymes, which represent the rate- feine intake, and cooperation bias from subjects. In limiting step for plasma clearance, and its elimination addition, results from these studies depend on subject follows first-order kinetics. P-450 1A2, which is coded for population selected. Whereas most of the studies used by the gene CYP1A2, is the primary isoenzyme responsible general community for sample population, the two studies for the demethylation of caffeine into dimethylxanthine by Swan et al. used male World War II veterans, which may metabolites paraxanthine, theobromine, and theophylline have certain characteristics different from the general (Lelo et al. ; Miners and Birkett ). Each of these population. Many of these studies are also restricted to metabolites is subjected to further demethylation into Caucasian subjects or conducted in Caucasian-predominant monomethylxanthines (Miners and Birkett Variation populations, making the result difficult to generalize to in the CYP1A2 activity, both within and between individ- uals, represents a major source of variability in pharmaco- In summary, the above studies estimate heritability for kinetics of caffeine. The clearance of caffeine can vary to caffeine-related effects and consumption to range from 0.34 up to 40-fold within and between individuals (Kalow and to 0.58, with the heritability for heavy caffeine consump- Tang ; Kashuba et al. . Notable exogenous tion conspicuously higher at 0.77. A few conclusions can factors that affect clearance include numerous drugs, medications, and smoking status (Grosso and Bracken mediated responses. The psychomotor stimulant effects of ), as well as caffeine itself (Berthou et al. ).
caffeine are due to antagonism of adenosine’s inhibitory Endogenous factors include pregnancy, ethnicity, and actions on the striatal D2 transmission (Ferre genetics. Asian and African populations, for instance, Recent research suggests adenosine acts mainly to fine- appear to metabolize caffeine at slower rate than Cauca- tune other synaptic transmission in the CNS. For instance, 1 A2A heteromers modulate glutamergic neurotransmis- Under physiological conditions, the main effects of sion (Ciruela et al. whereas A2A receptors have been caffeine are due to competitive inhibition of adenosine shown to affect GABAnergic and cholinergic transmission receptors, mainly A1 and A2A receptors (Daly et al. ).
(Kirk and Richardson Thus, in addition to variations Adenosine receptors are G-protein-coupled receptors locat- in the A1 and A2A receptor genes and genes involved in the ed ubiquitously throughout the body. Of the four receptors P450 enzymes, genetic variations in a number of other that have been identified (A1, A2A, A2B, and A3), the A1 neurotransmitter functions could influence responses to and A2A receptors are especially prominent in the central nervous system and are the primary targets of caffeine.
Activation of the Gi- or Go-coupled A1 causes inhibition of Genetic variations in caffeine metabolism adenyl cyclase and Ca2+ channels, whereas activation ofGs-coupled A2A causes activation of adenyl cyclase and voltage-sensitive Ca2+ channels (Fredholm et al. ).
Thus, A1 and A2A receptors possess partially opposing Since caffeine metabolism is mainly determined by the cytochrome enzyme P-450 1A2, genetic variations in this A1 receptors are widely distributed throughout the enzyme represent a major endogenous determinant of central nervous system. They are located on presynaptic enzyme activity. Early evidence for genetic variability on terminals and mediate inhibitory effects of adenosine on the CYP1A2 was first noted when a familial defect in O- release of other neurotransmitters, including glutamate deethylation, a marker reaction for CYP1A2, was reported (Marchi et al. acetylcholine (Kurokawa et al.
more than four decades ago (Devonshire et al. ; ), and dopamine (Yabuuchi et al. ). Caffeine Shahidi More recently, it has been shown that administration enhances acetylcholine release through its monozygotic twins share closer kinetic profile than dizy- effects on A1 receptors (Carter et al. ). A1 receptor gotic twins for caffeine metabolism, with an estimated blockade enhances the motor effects of D1 agonists (Fisone heritability of 0.725 (Rasmussen et al. More than et al. Fredholm et al. Accordingly, caffeine is 150 SNPs have been identified for CYP1A2 (dbSNP thought to produce its stimulatory and arousal effects by releasing this tonic inhibition of dopamine (Dunwiddie and conducted in different ethnic populations have shown large Masino Chronic treatment with caffeine results in variations in minor allele distributions and common upregulation of adenosine A1 receptors in the CNS, which haplotypes frequencies across different groups (Gunes and persists for 15–30 days after termination of caffeine administration (Boulenger et al. Marangos et al.
A single nucleotide C➔A polymorphism at position 734 ). Animal studies show that chronic administration of within intron 1 (rs762551) is correlated with high induc- caffeine produces multiple biochemical changes, including ibility of the P-450 1A2 enzyme in Caucasian subjects increased densities of A1 receptors, muscarinic and nico- (Sachse et al. Smoking subjects with A/A genotype tinic receptors, and increased benzodiazepine receptors metabolize caffeine at 1.6 times the rate of the other associated with GABAA in the brain (Shi et al. ). This genotypes, while no significant differences are found for upregulation is thought to be responsible for the tolerance nonsmoking subjects. The genetic polymorphism therefore modifies environmental impact on enzyme activity.
The A2A receptors, on the other hand, are located How does this allele influence caffeine response or primarily in regions rich in dopaminergic neurons, such as consumption? One study in Costa Rican subjects examined the striatum (Martinez-Mir et al. ). The receptors are whether the rs762551 single nucleotide polymorphism located postsynaptically on medium-sized spiny neurons in (SNP) was associated with coffee consumption but failed the striatum, which serves as the receiving unit of the basal to detect significant differences between the AA, AC, and ganglia (Fink et al. The basal ganglia controls CC genotypes (Cornelis et al. The study finding voluntary movement and motor behavior by relaying input suggested that rs762551 does not appear to be a major factor between the cortex and the thalamus. A2A receptors coloc- in determining individuals’ level of caffeine consumption.
alize postsynaptically with D2 receptors in the medium However, variations in CYP1A2 activity affect caffeine spiny neurons, and A2A blockade potentiates D2 receptor- response in other ways. As discussed below, there is evidence that CYP1A2 genotype modifies risk of certain caffeine administration than other groups (Alsene et al.
diseases associated with caffeine consumption (discussed A subsequent study using light-caffeine users confirmed this earlier positive association, though thisassociation was no longer significant when analysis was restricted to Caucasian subjects (Childs et al. ). Thestudy also found two other SNPs in ADORA2A (rs2298383 and rs4822492) to be associated with caffeine-inducedanxiety. Interestingly, therefore, two different alleles on Recent genetic studies in animals and humans have the same site, rs5751876, have been associated with two implicated polymorphisms in adenosine A1 and A2A different effects of caffeine—the C allele to caffeine- receptors in caffeine response. Animal studies show that induced sleep disturbance (Retey et al. and the T A2A receptors are involved in reinforcing behavioral effects allele to anxiety in Caucasian subjects (Alsene et al.
of caffeine and are also involved in mediating caffeine’s effect on the sleep cycle. More recently, human studies The associations between caffeine-induced anxiety and have shown that different A2A receptor polymorphisms are ADORA2A polymorphisms are especially intriguing when associated with caffeine-induced anxiety and sleep changes viewed in context of other studies linking ADORA2A to drug-induced anxiety and anxiety disorders. Both The adenosine A2A receptor plays a role in the effects of rs5751876 C/T and rs35320474 T/− polymorphisms have caffeine on arousal. Mice lacking functional A2A receptors been associated with increased anxiety after acute admin- do not show increased wakefulness in response to caffeine istration of amphetamine in healthy subjects (Hohoff et al.
administration, indicating that the A2A receptor mediates ). The rs5751876 T/T allele has been associated with the arousal response (Huang et al. In human panic disorder in Caucasian populations (Deckert et al.
subjects, the rs5751876 polymorphism in the A2A receptor ; Hamilton et al. although this association was is associated with sleep impairment and increased electro- not replicated in studies in Japanese (Yamada et al. encephalogram (EEG) beta band activity after caffeine and Chinese subjects (Lam et al. It is possible, then, administration (Retey et al. ). The ADORA2A that these genotypes play a role not just in caffeine-induced rs5751876 C/C (1976 C➔T, previously known as 1083 anxiety but also in anxiety and anxiety disorders overall in C➔T) genotype was found at greater prevalence in subjects certain populations. The finding that the same SNP is who rated themselves as caffeine sensitive, whereas a associated with both caffeine-induced anxiety and panic higher proportion of T/T genotype was found in self- disorder supports the observation that panic disorder reported insensitive subjects. Moreover, subjects who self- patients are particularly susceptible to caffeine-induced reported as caffeine sensitive also reported a greater rate of anxiety (Nardi et al. ) and suggests that polymor- caffeine-induced sleep impairment. Relationship between phisms in the A2A receptor may influence both.
caffeine sensitivity and sleep disturbance was collaborated A2A receptors are also involved in the rewarding by EEG finding of increased beta activity during non-REM properties of caffeine. A2A knockout mice self-administer sleep in C/C subjects, a pattern typically seen in insomnia less caffeine than wild-type animals (El Yacoubi et al.
patients (Merica Perlis et al. In contrast, ), suggesting a role for A2A receptors in the reinforcing subjects with C/T genotype showed half the increase in beta properties of caffeine. A cross-sectional study examining activity as compared to C/C genotype, and no change was the relationship between ADORA2A polymorphism and detected in T/T genotype. Therefore, genotype at caffeine consumption supports the idea that A2A receptors rs5751876 influenced risk of caffeine-induced insomnia.
may also be important for the negative reinforcement This correlation was independent of anxiety, although properties of caffeine in humans. A study in Costa Rican anxiety was reported with greater prevalence by caffeine- subjects without history of hypertension found that subjects sensitive individuals. While anxiety can itself be a factor in with rs5751876 T/T were likely to consume less caffeine insomnia, it was not correlated with ADORA2A genotype in than C/C subjects (Cornelis et al. However, the study did not screen the subjects for anxiety, which can Studies in human subjects suggest that polymorphisms itself affect consumption level and has also been linked to in the A2A receptor may be responsible for the negative rs5751876 T/T as described above. That anxiety can be a response to caffeine in certain individuals. The ADORA2A factor in caffeine consumption is supported by epidemio- SNPs rs5751876 and rs35320474 (2592 T/−) have been logical studies, which have shown panic disorder patients associated with anxiety in subjects who are light-caffeine consuming less caffeine than subjects without a history of users. Individuals with rs5751876 T/T and those with panic disorder (Arias Horcajadas et al. Lee et al.
rs35320474 T/T allele reported greater anxiety after acute protection, likely result from adaptive changes due to long-term use rather than from acute exposure. In this section, Caffeine administration in animal and human subjects we will examine the effects of chronic caffeine consump- produces effects, such as increased motor activity and tion on Parkinson’s and coronary heart diseases, two areas self-administration, similar to those of dopaminergically that have received significant attention and in which genetic mediated stimulants (Cauli and Morelli ; Garrett and studies in humans have been conducted.
Griffiths Interactions between adenosine and dopa- Case-control studies have noted an inverse correlation mine receptors play a key role in dopamine-potentiating between coffee drinking and Parkinson’s disease (Ascherio effects of caffeine. Dopamine D2 and adenosine A2A recep- et al. ; Ross et al. though this result has not tors colocalize in the dorsal and ventral striatal neurons and always been replicated (Checkoway et al. ). The form a heteromeric complex and exert antagonist effects on relationship appears to be dose dependent, with the each other via G-proteins (Fuxe et al. Dopamine is correlation strongest in heavy consumers. Studies in mice an important mediator of the locomotor stimulant effects of showed that physiological doses of caffeine were able to caffeine (Zahniser et al. ), and when given acutely, attenuate MPTP-induced dopaminergic toxicity (Chen et al.
caffeine can potentiate locomotor effects of dopamine- ). These properties were mimicked by A2A antagonists releasing agents (Kuribara ). The dopamine system is but not A1 antagonists, suggesting that neuroprotection implicated in the rewarding effects of cocaine and opioids, occurs via action at A2A receptor site. Similarly, A2A as well as natural rewards such as food and sex (Noble receptor knockout mice showed reduced MPTP-induced ). In animals, chronic caffeine administration enhances injury as compared to wild-type mice. The exact mecha- amphetamine and cocaine motor stimulant effects, as well nism of how A2A receptor antagonism can provide as discriminative effects of nicotine, suggesting long-term dopamine neuron protection remains unclear, but animal modification of dopamine receptors (Cauli and Morelli studies have shown that A2A receptor blockade protects Long-term administration of caffeine induces changes against ischemia neuronal injuries (Monopoli et al. ).
in tolerance or sensitization of dopamine-mediated responses Two studies have examined the association between A2A in rats (Fenu et al. ). Therefore, while caffeine does not polymorphisms and incidence of Parkinson’s. One study in bind directly to dopamine receptors, it is able to modulate Singaporean subjects found lower tea and coffee con- dopaminergic transmission indirectly via its action on the sumption in patients with Parkinson’s but did not detect differences in frequency of A2A rs35320474 (2592 T/−) Few studies have directly examined the effect of dopa- polymorphism between subjects with Parkinson’s and con- mine polymorphisms on caffeine response in human sub- trols (Tan et al. ). Another case-control study exam- jects. Childs et al. ) found that a polymorphism in ined rs5751876 and rs3032740 in ADORA2A and DRD2 (rs1110976) was associated with caffeine-induced rs35694136 and rs762551 in CYP1A2 and did not find anxiety in the Caucasian subjects. An interaction was re- any association between coffee drinking and risk of ported between ADORA2A rs5751876 and DRD2 rs1079597 Parkinson’s altogether, with or without accounting for that was associated with higher anxiety than either polymor- genotype (Facheris et al. While caffeine may offer phism alone. The gene–gene interaction is consistent with protection against Parkinson’s via A2A receptor, the lack of the animal models showing caffeine interacting with association between Parkinson’s and variants identified dopamine signaling via adenosine receptor.
with differential caffeine response suggests that neuro- The full extent of interaction between adenosine and protection may occur via a different mechanism from those dopamine receptors in caffeine response has not been fully elucidated. Caffeine has neuroprotective effects on dopami- The role of caffeine in cardiovascular disease has also nergic neurons via its interaction with A2A receptor, which been extensively studied. Acute ingestion of caffeine or may underlie the epidemiological finding that caffeine coffee, but not decaffeinated coffee, invokes a rise in consumption is inversely correlated with Parkinson’s disease, systolic and diastolic blood pressure, increases in catechol- amine release, and vasodilatation (Papamichael et al. ;Smits et al. ). However, effects of chronic caffeine Genetics and long-term effects of caffeine consumption in habitualized drinkers are quite different.
Some epidemiological studies find that regular coffee Polymorphisms that alter acute response to caffeine may intake slightly increases blood pressure (Jee et al. ; also affect long-term adaptations to caffeine use. While the Noordzij et al. while others find no difference.
role of acute caffeine response has been extensively Whether caffeine is implicated in cardiovascular diseases is studied, the effects of chronic consumption are less clear.
still being debated (Kawachi et al. ; Riksen et al. ; Several properties of caffeine, such as its role in neuro- Sofi et al. Despite its deleterious effects in acute settings, several large-scale studies have found that habitual metabolizing individuals could be at increased risk due to heavy use is protective against cardiovascular disease decreased ability to handle the stress associated with caffeine-induced catecholamine response. A summary of One possible factor for the contradictory findings was the results of polymorphisms associated with caffeine that different individuals have different risks, and genetics can modulate the risk of developing cardiovascular diseasefrom caffeine consumption. One study found that intake ofcaffeinated coffee was associated with increased risk of nonfatal myocardial infarction in individuals homozygousfor the slow allele CYP1A2*1F, marked by A➔C substitu- Genetic diversity can influence a response to caffeine and tion at position 734 (Cornelis et al. ). In another consumption pattern in many ways. It can confer vulnera- prospective study, the risk of acute myocardial infarction in bility to drug use, such as by modulating vulnerability to heavy coffee drinkers was found to be higher in subjects rewarding effects via the dopaminergic system. Diversity possessing allele for lower catechol-O-methyl transferase can also directly alter response such that the individual (COMT) activity (Happonen et al. ). COMT is the experiences caffeine more positively or negatively. Data main enzyme responsible for metabolism of catechol- from twin studies show that genetic predisposition toward amines, which characterize body’s response to physiolog- caffeine use acts mostly via a caffeine-specific mechanism.
ical and psychological stress and have been shown to Current research has implicated the primary enzyme in damage myocardial cells at high concentrations (Abraham caffeine metabolism, cytochrome P-450, and caffeine’s et al. Caffeine may represent a chemical stress to the main target receptors A1R and A2AR in variability in body due to its ability to potentiate catecholamine release caffeine response. Laboratory studies in human subjects (Lane et al. ). The finding of lower COMT activity show that susceptibility of some individuals to certain with higher risk of myocardial infarction points to involve- effects such as anxiety and insomnia can be accounted for ment of circulating catecholamines in caffeine’s effect on by specific alleles of the receptors. Case-control studies in cardiovascular system, with the implication that slow- habitual caffeine consumers show that genetics can modify Table 2 Polymorphisms linked to acute and chronic response to caffeine Intron I pos. 734: Increased activity in smokers with A/A genotype differ between the genotypes (Cornelis et al. ) Risk of nonfatal myocardial infarction higher for subjects with C/C genotype (Cornelis et al. No association found for risk of Parkinson’s No association found for risk of Parkinson’s C/C genotype associated with greater caffeine sensitivity, sleep impairment, and increased betaactivity during non-REM sleep (Retey et al. T/T genotype associated with greater anxiety after caffeine (Alsene et al. Childs et al. T/T genotype associated with greater anxiety No association found for Parkinson’s disease No association found for risk of Parkinson’s Associated with greater levels of caffeine-induced Nucleotide codon Higher risk of acute myocardial infarction in alleles coding for low activity (Met/Met)(Happonen et al. ) risks to certain health outcomes associated with chronic From these studies, it is clear that studying the genetic basis for caffeine response not only enhances our under-standing of the mechanism of action for caffeine itself butalso to the biochemical function of the receptors and their associated neurotransmitters. In addition, these studies havealso led to new fields in biomedical research: how genetics The widespread use of caffeine makes it an important target influences response to drugs and sheds new light on in understanding human health and disease. Progress has pathophysiology of commonly studied diseases. Further been made in understanding variability in caffeine research is needed to understand the functional significance responses related to the metabolic enzyme P-450, adenosine of these genotypes and the interaction between the drug, receptors A1 and A2A, and to a more limited extent, dopamine. Further research is likely to identify othersources of variation related to the metabolic enzymes,adenosine receptors, and interactions with dopamine, This research was supported by NIDA (DA021336 and DA02812). All authors reported no biomedical interests or potential GABAA, and muscarinic and nicotinic receptors.
One area that has received little attention is genotype effects in different populations. Due to concerns aboutsubject population and/or population stratification, most of the research has been limited to single ethnicities. However,wide ethnic variations are found for CYP1A2 polymor- Abraham J, Mudd JO, Kapur N, Klein K, Champion HC, Wittstein IS phisms, and there appear to be variations in the association (2009) Stress cardiomyopathy after intravenous administration of between ADORA2A SNP rs5751876 and caffeine-induced catecholamines and beta-receptor agonists. J Am Coll Cardiol53:1320–1325 anxiety in different ethnic groups (Lam et al. Yamada Alsene K, Deckert J, Sand P, de Wit H (2003) Association between et al. More studies in non-Caucasian ethnicities are A2a receptor gene polymorphisms and caffeine-induced anxiety.
needed to complete our understanding of genotype effects Andersen LF, Jacobs DR Jr, Carlsen MH, Blomhoff R (2006) Consumption of coffee is associated with reduced risk of death One of the most exciting directions coming out of attributed to inflammatory and cardiovascular diseases in the caffeine research may be identifying new targets in Iowa Women’s Health Study. Am J Clin Nutr 83:1039–1046 studying pathogenesis of neurodegenerative disorders. The Arias Horcajadas F, Sánchez Romero S, Padìn Calo J, Fernández-Rojo linkage of adenosine receptor to Parkinson’s disease has led S, Fernández Martìn G (2005) Psychoactive drugs use in patientswith panic disorder. Actas Esp Psiquiatr 33:160–164 to stage III clinical trial testing the adenosine A2A Arnaud MJ (1987) The pharmacology of caffeine. Prog Drug Res antagonist istradefylline (KW6002) as a new therapeutic option (LeWitt et al. ). The same ADORA2A SNP that Ascherio A, Zhang SM, Hernán MA, Kawachi I, Colditz GA, Speizer has been found to be related to caffeine-induced anxiety has FE, Willett WC (2001) Prospective study of caffeine consump-tion and risk of Parkinson’s disease in men and women. Ann also been associated with age of onset for Huntington’s disease (Dhaenens et al. It is still unclear why there Bchir F, Dogui M, Ben Fradj R, Arnaud MJ, Saguem S (2006) would be a relationship between A2A receptor and onset for Differences in pharmacokinetic and electroencephalographic Huntington’s disease; however, several recent studies have responses to caffeine in sleep-sensitive and non-sensitive sub-jects. CR Biol 329:512–519 supported the hypothesis that A2A receptors play a role in Benowitz NL (1990) Clinical pharmacology of caffeine. Annu Rev neuronal development in Huntington’s disease (Popoli et al.
). One future direction would be to examine whether Berthou F, Goasduff T, Dréano Y, Ménez J-F (1995) Caffeine caffeine has protective effects against other forms of increases its own metabolism through cytochrome P4501Ainduction in rats. Life Sci 57:541–549 neurological disorders and dementia.
Boulenger JP, Patel J, Post RM, Parma AM, Marangos PJ (1983) Finally, knowledge from studying caffeine can be used Chronic caffeine consumption increases the number of brain to explore other drugs. Theophylline, a similarly structured adenosine receptors. Life Sci 32:1135–1142 methylxanthine and a minor metabolite of caffeine are used Bruce M, Scott N, Shine P, Lader M (1992) Anxiogenic effects of caffeine in patients with anxiety disorders. Arch Gen Psychiatry to treat asthma, especially in the pediatric population.
However, its use is complicated by narrow therapeutic Carmelli D, Swan GE, Robinette D, Fabsitz RR (1990) Heritability of window and potential toxicity. Like caffeine, theophylline substance use in the NAS-NRC Twin Registry. Acta Genet Med clearance is mainly determined by P-450 activity (Obase et Carter AJ, O’Connor WT, Carter MJ, Ungerstedt U (1995) Caffeine al. ). Studying the genetic polymorphisms affecting enhances acetylcholine release in the hippocampus in vivo by a theophylline response could provide a better means to selective interaction with adenosine A1 receptors. J Pharmacol Cauli O, Morelli M (2005) Caffeine and the dopaminergic system.
Fenu S, Cauli O, Morelli M (2000) Cross-sensitization between the motor activating effects of bromocriptine and caffeine: role of Charney DS, Heninger GR, Jatlow PI (1985) Increased anxiogenic adenosine A2A receptors. Behav Brain Res 114:97–105 effects of caffeine in panic disorders. Arch Gen Psychiatry Ferre S (2008) An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem 105:1067–1079 Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth Fink JS, Weaver DR, Rivkees SA, Peterfreund RA, Pollack AE, Adler WT Jr, Swanson PD (2002) Parkinson’s disease risks associated EM, Reppert SM (1992) Molecular cloning of the rat A2 with cigarette smoking, alcohol consumption, and caffeine adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res Mol Brain Res 14:186–195 Chen J-F, Xu K, Petzer JP, Staal R, Xu Y-H, Beilstein M, Sonsalla PK, Fisone G, Borgkvist A, Usiello A (2004) Caffeine as a psychomotor Castagnoli K, Castagnoli N Jr, Schwarzschild MA (2001) stimulant: mechanism of action. Cell Mol Life Sci 61:857–872 Neuroprotection by caffeine and A2A adenosine receptor Frary CD, Johnson RK, Wang MQ (2005) Food sources and intakes of inactivation in a model of Parkinson’s disease. J Neurosci caffeine in the diets of persons in the United States. J Am Diet Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999) Association between ADORA2A and DRD2 polymorphisms and Actions of caffeine in the brain with special reference to caffeine-induced anxiety. Neuropsychopharmacology 33:2791– factors that contribute to its widespread use. Pharmacol Rev Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, Fuxe K, Agnati LF, Jacobsen K, Hillion J, Canals M, Torvinen M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortes A, Canela EI, Tinner-Staines B, Staines W, Rosin D, Terasmaa A, Popoli P, Leo Lopez-Gimenez JF, Milligan G, Lluis C, Cunha RA, Ferre S, G, Vergoni V, Lluis C, Ciruela F, Franco R, Ferre S (2003) Franco R (2006) Presynaptic control of striatal glutamatergic Receptor heteromerization in adenosine A2A receptor signaling: neurotransmission by adenosine A1–A2A receptor heteromers. J relevance for striatal function and Parkinson’s disease. Neurology Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H (2006) Garrett BE, Griffiths RR (1997) The role of dopamine in the Coffee, CYP1A2 genotype, and risk of myocardial infarction.
behavioral effects of caffeine in animals and humans. Pharmacol Cornelis MC, El-Sohemy A, Campos H (2007) Genetic polymorphism Griffiths RR, Woodson PP (1988) Reinforcing effects of caffeine in of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr 86:240–244 Grosso LM, Bracken MB (2005) Caffeine metabolism, genetics, and Daly JW, Fredholm BB (1998) Caffeine—an atypical drug of perinatal outcomes: a review of exposure assessment consid- dependence. Drug Alcohol Depend 51:199–206 erations during pregnancy. Ann Epidemiol 15:460–466 Daly JW, Buttslamb P, Padgett W (1983) Subclasses of adenosine Gunes A, Dahl ML (2008) Variation in CYP1A2 activity and its receptors in the central nervous-system—interaction with caf- clinical implications: influence of environmental factors and feine and related methylxanthines. Cell Mol Neurobiol 3:69–80 genetic polymorphisms. Pharmacogenomics 9:625–637 Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M, Maier Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge W, Beckmann H, Propping P (1998) Systematic mutation SE, Weissman MM, Fyer AJ, Knowles JA (2004) Evidence for screening and association study of the A1 and A2a adenosine genetic linkage between a polymorphism in the adenosine 2A receptor genes in panic disorder suggest a contribution of the A2a receptor and panic disorder. Neuropsychopharmacology 29:558– gene to the development of disease. Mol Psychiatry 3:81–85 Devonshire HW, Kong I, Cooper M, Sloan TP, Idle JR, Smith RL Hansen JL, Reed DR, Wright MJ, Martin NG, Breslin PA (2006) (1983) The contribution of genetically determined oxidation Heritability and genetic covariation of sensitivity to PROP, SOA, status to inter-individual variation in phenacetin disposition. Br J quinine HCl, and caffeine. Chem Senses 31:403–413 Happonen P, Voutilainen S, Tuomainen TP, Salonen JT (2006) Dhaenens CM, Burnouf S, Simonin C, Van Brussel E, Duhamel A, Catechol-o-methyltransferase gene polymorphism modifies the Defebvre L, Duru C, Vuillaume I, Cazeneuve C, Charles P, effect of coffee intake on incidence of acute coronary events.
Maison P, Debruxelles S, Verny C, Gervais H, Azulay JP, Tranchant C, Bachoud-Levi AC, Durr A, Buee L, Krystkowiak P, Hartley TR, Sung BH, Pincomb GA, Whitsett TL, Wilson MF, Sablonniere B, Blum D (2009) A genetic variation in the Lovallo WR (2000) Hypertension risk status and effect of ADORA2A gene modifies age at onset in Huntington’s disease.
caffeine on blood pressure. Hypertension 36:137–141 Haskell CF, Kennedy DO, Wesnes KA, Scholey AB (2005) Cognitive Dunwiddie TV, Masino SA (2001) The role and regulation of and mood improvements of caffeine in habitual consumers and adenosine in the central nervous system. Annu Rev Neurosci habitual non-consumers of caffeine. Psychopharmacology (Berl) El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois J-M Hettema JM, Corey LA, Kendler KS (1999) A multivariate genetic (2005) Reduced appetite for caffeine in adenosine A2A receptor analysis of the use of tobacco, alcohol, and caffeine in a knockout mice. Eur J Pharmacol 519:290–291 population based sample of male and female twins. Drug Alcohol Evans S, Griffiths R (1992) Caffeine tolerance and choice in humans.
Hohoff C, McDonald JM, Baune BT, Cook EH, Deckert J, de Wit H Facheris MF, Schneider NK, Lesnick TG, Md A, Cunningham JM, (2005) Interindividual variation in anxiety response to amphet- Rocca WA, Maraganore DM (2008) Coffee, caffeine-related amine: possible role for adenosine A2A receptor gene variants.
genes, and Parkinson’s disease: a case-control study. Mov Disord Am J Med Genet B Neuropsychiatr Genet 139B:42–44 Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Farag NH, Vincent AS, McKey BS, Whitsett TL, Lovallo WR (2005) Fredholm BB, Urade Y, Hayaishi O (2005) Adenosine A2A, Hemodynamic mechanisms underlying the incomplete tolerance but not A1, receptors mediate the arousal effect of caffeine. Nat to caffeine’s pressor effects. Am J Cardiol 95:1389–1392 Jee SH, He J, Whelton PK, Suh I, Klag MJ (1999) The effect of disease: a double-blind, randomized, multicenter clinical trial chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension 33:647–652 Lieberman HR, Wurtman RJ, Emde GG, Roberts C, Coviella ILG Kalow W, Tang BK (1991) Use of caffeine metabolite ratios to (1987) The effects of low doses of caffeine on human explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol performance and mood. Psychopharmacology 92:308–312 Lieberman HR, Tharion WJ, Shukitt-Hale B, Speckman KL, Tulley R Kashuba AD, Bertino JS Jr, Kearns GL, Leeder JS, James AW, (2002) Effects of caffeine, sleep loss, and stress on cognitive Gotschall R, Nafziger AN (1998) Quantitation of three-month performance and mood during U.S. Navy SEAL training. Sea– intraindividual variability and influence of sex and menstrual Air–Land. Psychopharmacology (Berl) 164:250–261 cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine Lovallo WR, Wilson MF, Vincent AS, Sung BH, McKey BS, Whitsett oxidase activity determined with caffeine phenotyping. Clin TL (2004) Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension Kawachi I, Colditz GA, Stone CB (1994) Does coffee drinking increase the risk of coronary heart disease? Results from a meta- Luciano M, Kirk KM, Heath AC, Martin NG (2005) The genetics of tea and coffee drinking and preference for source of caffeine in a Kendler KS (1993) Twin studies of psychiatric illness: current status large community sample of Australian twins. Addiction and future directions. Arch Gen Psychiatry 50:905–915 Kendler KS, Prescott CA (1999) Caffeine intake, tolerance, and Luciano M, Zhu G, Kirk KM, Gordon SD, Heath AC, Montgomery withdrawal in women: a population-based twin study. Am J GW, Martin NG (2007) “No thanks, it keeps me awake”: the genetics of coffee-attributed sleep disturbance. Sleep 30:1378– Kendler KS, Heath AC, Martin NG, Eaves LJ (1987) Symptoms of anxiety and symptoms of depression: same genes, different Maia L, de Mendonca A (2002) Does caffeine intake protect from environments? Arch Gen Psychiatry 44:451–457 Alzheimer’s disease? Eur J Neurol 9:377–382 Kendler KS, Myers J, Prescott CA (2007) Specificity of genetic and Marangos PJ, Boulenger JP, Patel J (1984) Effects of chronic caffeine environmental risk factors for symptoms of cannabis, cocaine, on brain adenosine receptors: regional and ontogenetic studies.
alcohol, caffeine, and nicotine dependence. Arch Gen Psychiatry Marchi M, Raiteri L, Risso F, Vallarino A, Bonfanti A, Monopoli A, Kendler KS, Schmitt E, Aggen SH, Prescott CA (2008) Genetic and Ongini E, Raiteri M (2002) Effects of adenosine A1 and A2A environmental influences on alcohol, caffeine, cannabis, and receptor activation on the evoked release of glutamate from rat nicotine use from early adolescence to middle adulthood. Arch cerebrocortical synaptosomes. Br J Pharmacol 136:434–440 Martinez-Mir MI, Probst A, Palacios JM (1991) Adenosine A2 Kirk IP, Richardson PJ (1994) Adenosine A2a receptor-mediated receptors: selective localization in the human basal ganglia and modulation of striatal GABA and acetylcholine release. J alterations with disease. Neuroscience 42:697–706 Merica H (1998) Spectral characteristics of sleep EEG in chronic Klatsky AL, Friedman GD, Armstrong MA (1990) Coffee use prior to myocardial infarction restudied: heavier intake may increase the Migliardi JR, Armellino JJ, Friedman M, Gillings DB, Beaver WT (1994) Caffeine as an analgesic adjuvant in tension headache.
Kuribara H (1994) Modification by caffeine of the sensitization to methamphetamine and cocaine in terms of ambulation in mice.
Miners JO, Birkett DJ (1996) The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Gen Pharmacol 27:245– Kurokawa M, Shiozaki S, Nonaka H, Kase H, Nakamura J, Kuwana Y (1996) In vivo regulation of acetylcholine release via adenosine Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E (1998) A1 receptor in rat cerebral cortex. Neurosci Lett 209:181–184 Blockade of adenosine A2A receptors by SCH 58261 results in Laitala VS, Kaprio J, Silventoinen K (2008) Genetics of coffee neuroprotective effects in cerebral ischaemia in rats. NeuroReport consumption and its stability. Addiction 103:2054–2061 Lam P, Hong CJ, Tsai SJ (2005) Association study of A2a adenosine Mosqueda-Garcia R, Robertson D, Robertson RM (1993) The receptor genetic polymorphism in panic disorder. Neurosci Lett cardiovascular effects of caffeine. In: Garattini S (ed) Caffeine, coffee, and health. Raven, New York, pp 157–176 Lane JD, Adcock RA, Williams RB, Kuhn CM (1990) Caffeine Nardi AE, Lopes FL, Freire RC, Veras AB, Nascimento I, Valença effects on cardiovascular and neuroendocrine responses to acute AM, de-Melo-Neto VL, Soares-Filho GL, King AL, Araùjo DM, psychosocial stress and their relationship to level of habitual Mezzasalma MA, Rassi A, Zin WA (2009) Panic disorder and caffeine consumption. Psychosom Med 52:320–336 social anxiety disorder subtypes in a caffeine challenge test.
Lee MA, Cameron OG, Greden JF (1985) Anxiety and caffeine consumption in people with anxiety disorders. Psychiatry Res Neale MC, Cardon LR (1992) Methodology for genetic studies of Lee M, Flegel P, Greden J, Cameron O (1988) Anxiogenic effects of Noble EP (2000) Addiction and its reward process through poly- caffeine on panic and depressed patients. Am J Psychiatry morphisms of the D2 dopamine receptor gene: a review. Eur Lelo A, Birkett DJ, Robson RA, Miners JO (1986) Comparative Noordzij M, Uiterwaal CS, Arends LR, Kok FJ, Grobbee DE, pharmacokinetics of caffeine and its primary demethylated Geleijnse JM (2005) Blood pressure response to chronic intake metabolites paraxanthine, theobromine and theophylline in man.
of coffee and caffeine: a meta-analysis of randomized controlled LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P, Nurminen ML, Niittynen L, Korpela R, Vapaatalo H (1999) Coffee, Sussman NM (2008) Adenosine A2A receptor antagonist caffeine and blood pressure: a critical review. Eur J Clin Nutr istradefylline (KW-6002) reduces “off” time in Parkinson’s Obase Y, Shimoda T, Kawano T, Saeki S, S-y T, Mitsuta-Izaki K, Silverman K, Griffiths RR (1992) Low-dose caffeine discrimination Matsuse H, Kinoshita M, Kohno S (2003) Polymorphisms in the and self-reported mood effects in normal volunteers. J Exp Anal CYP1A2 gene and theophylline metabolism in patients with Smits P, Thien T, Van ’t Laar A (1985) The cardiovascular effects of Papamichael CM, Aznaouridis KA, Karatzis EN, Karatzi KN, regular and decaffeinated coffee. Br J Clin Pharmacol 19:852– Stamatelopoulos KS, Vamvakou G, Lekakis JP, Mavrikakis ME (2005) Effect of coffee on endothelial function in healthy Sofi F, Conti AA, Gori AM, Eliana Luisi ML, Casini A, Abbate R, subjects: the role of caffeine. Clin Sci (Lond) 109:55–60 Gensini GF (2007) Coffee consumption and risk of coronary Perlis ML, Merica H, Smith MT, Giles DE (2001) Beta EEG activity heart disease: a meta-analysis. Nutr Metab Cardiovasc Dis Popoli P, Blum D, Domenici MR, Burnouf S, Chern Y (2008) A Swan GE, Carmelli D, Cardon LR (1996) The consumption of critical evaluation of adenosine A2A receptors as potentially tobacco, alcohol, and coffee in Caucasian male twins: a “druggable” targets in Huntington’s disease. Curr Pharm Des multivariate genetic analysis. J Subst Abuse 8:19–31 Swan GE, Carmelli D, Cardon LR (1997) Heavy consumption of Rasmussen BB, Brix TH, Kyvik KO, Brøsen K (2002) The cigarettes, alcohol and coffee in male twins. J Stud Alcohol interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental Swanson JA, Lee JW, Hopp JW (1994) Caffeine and nicotine: a factors. Pharmacogenet Genomics 12:473–478 review of their joint use and possible interactive effects in Retey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, tobacco withdrawal. Addict Behav 19:229–256 Landolt HP (2007) A genetic variation in the adenosine A2A Tan EK, Lu ZY, Fook-Chong SMC, Tan E, Shen H, Chua E, Yih Y, receptor gene (ADORA2A) contributes to individual sensitivity Teo YY, Zhao Y (2006) Exploring an interaction of adenosine to caffeine effects on sleep. Clin Pharmacol Ther 81:692–698 A2A receptor variability with coffee and tea intake in Parkinson’s Riksen NP, Rongen GA, Smits P (2009) Acute and long-term disease. Am J Med Genet B Neuropsychiatr Genet 141B:634– cardiovascular effects of coffee: implications for coronary heart Teucher B, Skinner J, Skidmore PM, Cassidy A, Fairweather-Tait SJ, Robertson D, Wade D, Workman R, Woosley RL, Oates JA (1981) Hooper L, Roe MA, Foxall R, Oyston SL, Cherkas LF, Perks Tolerance to the humoral and hemodynamic effects of caffeine in UC, Spector TD, MacGregor AJ (2007) Dietary patterns and heritability of food choice in a UK female twin cohort. Twin Res Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung K-H, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Vink JM, Staphorsius AS, Boomsma DI (2009) A genetic analysis of Popper JS, White LR (2000) Association of coffee and caffeine coffee consumption in a sample of Dutch twins. Twin Res Hum intake with the risk of Parkinson disease. JAMA 283:2674–2679 Sachse C, Brockmöller J, Bauer S, Roots I (1999) Functional Yabuuchi K, Kuroiwa M, Shuto T, Sotogaku N, Snyder GL, significance of a C–>A polymorphism in intron 1 of the Higashi H, Tanaka M, Greengard P, Nishi A (2006) Role of cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum. Neuro- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, the Caffeine for Apnea of Prematurity Yamada K, Hattori E, Shimizu M, Sugaya A, Shibuya H, Yoshikawa Trial Group (2007) Long-term effects of caffeine therapy for T (2001) Association studies of the cholecystokinin B receptor apnea of prematurity. N Engl J Med 357:1893–1902 and A2a adenosine receptor genes in panic disorder. J Neural Shahidi NT (1967) Acetophenetidin sensitivity. Am J Dis Child Zahniser NR, Simosky JK, Mayfield RD, Negri CA, Hanania T, Shi D, Nikodijević O, Jacobson KA, Daly JW (1993) Chronic caffeine Larson GA, Kelly MA, Grandy DK, Rubinstein M, Low MJ, alters the density of adenosine, adrenergic, cholinergic, GABA, Fredholm BB (2000) Functional uncoupling of adenosine A2A and serotonin receptors and calcium channels in mouse brain.
receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. J Neurosci 20:5949–5957

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