aPlasmatic concentrations of caffeine attained after recreational consumption of moderate amounts of the substance are estimated to be considerably below 0.1 mM
bMay significantly drop in the presence of glucose cDifferences may exist between liver and muscle enzymes dMay significantly vary among different isoforms the ability of caffeine in influencing the execution of tests aimed at evaluating either memory or attention can be used to study the effects of caffeine on cognitive performance (► rodent models of cognition). Either acute or chronic changes in animals' behavior as measured by means of the above paradigms can also be used to ascertain whether, and to what extent, exposure to caffeine modulates the effects elicited by other psychoactive substances. Finally, the study of the conditions favoring the instatement and maintenance of a caffeine consumption habit (► caffein-ism) is also possible in animals. This can be performed in either rodents or primates by means of the ► drug self-administration paradigm (Fredholm et al. 1999).
The majority of the investigations dealing with the effects of caffeine in humans are concerned with its ► psychostimulant and rewarding effects. The conditions under which caffeine delays the need for sleep and promotes alertness in sleep-deprived individuals are extensively investigated and so are the effects of caffeine on mood and on the execution of mental tasks. Such investigations usually employ a single administration or a brief multiple exposure to caffeine, and are often paired with electroencephalo-graphic analysis (► electroencephalography) to examine the pattern of caffeine-induced neuronal activation. Moreover, investigations can be conducted to address either the features of ► caffeine withdrawal syndrome (► withdrawal syndromes) or the influence of caffeine intake on the neurobehavioral effects of other centrally active substances. Peripheral effects of caffeine can be evaluated in humans as well, and consumption of caffeine is usually included as a variable in epidemiological studies, in light of the widespread diffusion of this habit (Fredholm et al. 1999).
Caffeine is rapidly and nearly completely absorbed after oral intake. In adult healthy humans, caffeine reaches its plasmatic concentration peak within 0.5-2 h from ingestion. Plasmatic ► half-life of caffeine is estimated for 210 h in young adults and elders, while it is higher in neonates and infants, due to the incomplete development of metabolic pathways in these subjects. As it displays lipophilic properties, caffeine crosses the ► blood-brain barrier and can reach the brain at high concentrations. Furthermore, caffeine penetrates the placenta, thus reaching the fetus. Significant levels of caffeine can be also detected in milk and saliva.
Caffeine is mainly metabolized by the ► cytochrome P-450 hepatic enzymes. Several active caffeine metabolites have been isolated, the major being theophylline, theo-bromine, and paraxanthine, and interspecies differences in caffeine metabolism exist. Many of caffeine metabolites display a pharmacological profile close to the one of their parent compound, and can participate in caffeine effects. In humans, the main metabolic pathway of caffeine involves its degradation to paraxanthine which is catalyzed by the CYP1A2 subform of the P-450 enzymes.
Conditions influencing the function of P-450 enzymes can profoundly impact the metabolism and, accordingly, the ► pharmacokinetics of caffeine. Caffeine plasmatic half-life is increased by diseases depressing hepatic metabolic activity (e.g., cirrhosis) and by agents that are metabolized by, or that inhibit, the CYP1A2 (e.g., cimetidine, ► disulfiram, estrogens). Conversely, a reduction in caffeine half-life is caused by agents capable of inducing P-450 enzymes (e.g., ► carbamazepine, rifampicin, cigarette smoke) (Fredholm et al. 1999; Magkos and Kavouras 2005).
Consumption of caffeine is considered a safe habit, since the lethal dose of the substance is very high (at least 100 mg/kg). Nevertheless, cases of either poisoning or anaphylaxis induced by caffeine have been reported, and adverse effects may be associated with recreational caffeine consumption. Irritability, anxiety, psychotic-like symptoms, and increased susceptibility to seizures have been described in caffeine consumers. These effects are likely manifested in the presence of a pre-existing individual susceptibility; hence, their incidence is negligible though it can increase when caffeine is consumed at high doses. In addition, caffeine elevates blood pressure and can, at times, trigger alterations in heart rhythm (Higdon and Frei 2006). Rodent studies have suggested that caffeine consumption during pregnancy might promote teratogenesis, but this hypothesis has not been proven conclusively in humans. Similarly, neither has caffeine intake been convincingly demonstrated to increase the risk of abortion. However, moderation in caffeine consumption is advisable in pregnant women to prevent the fetus from being reached by caffeine which could exert adverse effects on it.
Caffeine can influence the pharmacological effects of several drugs. This may happen through mechanisms involving metabolism (see above), clearance (e.g., lithium), absorption (e.g., oral iron supplements), or pharmacodynamic amplification of other drugs' effects (e.g., ephedrine). In its recreational use, caffeine is often associated with other psychostimulants, as amphetamine analogs, to increase their effects, or to alcohol, to counteract alcohol depressive effects and hangover. In both cases, use of caffeine may produce severe side effects by raising the toxicity of amphetamine analogs (e.g., ► MDMA) or letting the alcohol consumer to increase the assumption of alcohol up to toxic doses.
The major uses of caffeine as a medication are as analgesic for the treatment of headache and as a respiratory stimulant for the management of postpartum apnea in premature neonates. Furthermore, due to its lipolitic and thermogenetic properties, caffeine is an adjuvant in topic anti-cellulite preparations and its use has been suggested for the treatment of obesity. The use of caffeine to counteract some aspects of ► akinesia and tremor associated with Parkinson's disease has also been proposed.
Caffeine is widely employed in biomedical research. Thus, caffeine is a standard molecule in studies investigating the pharmacology of adenosine receptors, due to its reduced cost and good solubility in physiological mediums. Furthermore, activation of the ryanodine receptor, which modulates Ca2+ release from intracellular stores, by caffeine is exploited to investigate muscular physiopathology and mechanisms of cellular Ca2+ turnover. Caffeine is also used in biopharmaceutical studies evaluating the permeability of the skin and artificial skinlike membranes, due to its well-characterized biophysical properties. Measurement ofthe clearance ofcaffeine and/or its metabolites is employed to estimate hepatic and/or renal functionality, while quantification of caffeine degradation to paraxanthine is used as a phenotypic marker for the CYP1A2 enzyme. Moreover, changes in the susceptibility of the skeletal muscle to caffeine-induced contraction are evaluated as a diagnostic parameter for malignant hyper-thermia.
Caffeine is one of the most popular psychostimulant substances in the world. Although caffeine consumption is generally not associated with harmful consequences, moderation in caffeine intake is advisable to selected categories of individuals, such as pregnant women or persons particularly susceptible to its adverse effects. Finally, the ability of caffeine in interfering with the effects of centrally active substances, including addictive psychostimulants, may represent a further risk factor associated with its consumption.
► Conditioned Place Preference and Aversion
► Conditioned Taste Aversion and Preference
► Drug Discrimination
► Intracranial Self-Stimulation
► Pharmacodynamic Tolerance
► Psychomotor Stimulants
► Rodent Models of Cognition
► Self-Administration of Drugs
► Withdrawal Syndromes
Cauli O, Morelli M (2005) Caffeine and the dopaminergic system. Behav
Pharmacol 16:63-77 Ferre S, Fredholm BB, Morelli M, Popoli P, Fuxe K (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20:482-487 Fisone G, Borgkvist A, Usiello A (2004) Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci 61:857-872
Fredholm BB, Svenningsson P (2003) Adenosine-dopamine interactions: development of a concept and some comments on therapeutic possibilities. Neurology 61(11 Suppl 6):S5-S9 Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83-133 Higdon JV, Frei B (2006) Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr 46:101-123 Higgins GA, Grzelak ME, Pond AJ, Cohen-Williams ME, Hodgson RA, Varty GB (2007) The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A2A receptors. Behav Brain Res 185:32-42 Magkos F, Kavouras SA (2005) Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr 45:535-562
Schwarzschild MA, Ascherio A (2004) Caffeine and Parkinson's disease. In: Nehlig A (ed) Coffee, tea, chocolate, and the brain. CRC Press, Boca Raton, pp 147-164 Zahniser NR, Simosky JK, Mayfield RD, Negri CA, Hanania T, Larson GA, Kelly MA, Grandy DK, Rubinstein M, Low MJ, Fredholm BB (2000) Functional uncoupling of adenosine A(2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. J Neurosci 20:5949-5957
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