Caffeine, also known as 1,3,7-trimethylxanthine, is an alkaloid and one of the most widely used drugs around the world. It has been consumed since ancient times due to its beneficial effects on attention, psychomotor function, and memory.
Caffeine Sources, Absorption, Distribution, Pharmacokinetics and Metabolism.
Caffeine is present in a number of dietary sources consumed worldwide like tea, coffee, cocoa beverages, chocolate bars, and soft drinks. The content of caffeine of these various food items ranges from 40 to 180 mg/150 ml for coffee to 24 to 50 mg/150 ml for tea, 15 to 29 mg/180 ml for cola, 2 to 7 mg/150 ml for cocoa, and 1 to 36 mg/28 g for chocolate. Caffeine consumption; J.J. Baronea, H.R.
In humans Caffeine absorption in the gastrointestinal tract is rapid and reaches 99% in about 45 minutes after ingestion, plasmatic peak concentration is reached between 15 and 120 min and half lives is between 2.5 and 4.5 hours. Because the molecule is hydrophobic, it passes through all biological barriers. In fact there is no blood-brain barrier and no placental barrier for this alkaloid. The pharmacology of caffeine; M. J. Arnaud
Caffeine is metabolized by the liver to form dimethyl- and monomethylxanthines, dimethyl and monomethyl uric acids, trimethyl- and dimethylallantoin, and uracil derivatives. In humans the quantitative most important reaction is the 3-methyl demethylation leading to the formation of paraxanthine. The pharmacology of caffeine; M. J. Arnaud
Metabolites like teophylline (1,3-dimethylxanthine) and paraxanthine (1,7-dimethylxanthine) also have pharmacological activity. Sympathomimetic effects of paraxanthine and caffeine in humans; Neal L. Benowitz MD, Peyton Jacob III PhD, Haim Mayan MD, Charles Denaro
Molecular and Cellular Action of Caffeine on the Brain
The only known molecular effect of caffeine at a concentration normally achieved after moderate oral consumption is binding to adenosine receptors and antagonism of the actions of agonists at these receptors. Are methylxanthine effects due to antagonism of endogenous adenosine?; Bertil B. Fredholm
Other effects on the cellular level emerge at higher doses (millimolar plasma concentrations) and are:
• Direct release of intracellular calcium (probably via an action on ryanodine receptors); The brain ryanodine receptor: A caffeine-sensitive calcium release channel; Peter S. McPhersonx, Young-Kee Kim, Hector Valdivia, C.Michael Knudson, Hiroaki Takekura, Clara Franzini-Armstrong, Roberto Coronadot, Kevin P. Campbell
• Inhibition of cyclic nucleotide phosphodiesterases; Are methylxanthine effects due to antagonism of endogenous adenosine?; Bertil B. Fredholm.
• Influence 5'-nucleotidase and alkaline phosphatase; Inhibition of soluble 5′-nucleotidase from rat brain by different xanthine derivatives; Bertil B. Fredholm, Eva Lindgren.
Because in the normal human coffee consumption the major effects of caffeine are on adenosine receptors, we will now discuss the effects of agonist on these receptors, their fundamental biochemical actions, their localization and their roles in the mammalian brain. Knowing all this is easy to comprehend the effects of caffeine.
At present four distinct adenosine receptors, A1, A2A, A2B, and A3, have been cloned and characterized in several species.
In humans, the A3 receptor is blocked by caffeine with a KD of close to 80 µM. Therefore, this receptor is not the best target for caffeine actions in humans. The A2B receptor has been shown to require higher concentrations of adenosine for activation than those found in resting animal tissues. Inhibition of adenosine actions at this receptor is similarly unlikely to provide an explanation for the actions of caffeine under physiological conditions.
A1 and A2A receptors are activated at the low basal adenosine concentrations measured in resting rat brain. Thus, these receptors are likely to be the major targets for caffeine. Nomenclature and Classification of Purinoceptors; B.B. Fredholm, M.P. Abbracchio, G. Burnstock, J.W. Daly, T.K. Harden, K.A. Jacobson, P. Leff, M. Williams
A1 and A2A receptors are both G-protein-coupled:
• A1 receptors are coupled to pertussis toxin sensitive G proteins. So activation of A1 receptors cause inhibition of adenylyl cyclase and of at least some types of voltage-sensitive C²⁺-channels such as the N- and the Q-channels, and activation of several types of K⁺-channels, phospholipase C and phospholipase D.
• A2 receptors are coupled to Gs-proteins. Activation of these receptors causes the activation of adenylyl cyclase and perhaps also activation of some types of voltage-sensitive Ca²⁺-channels, especially the L-channel. Nomenclature and Classification of Purinoceptors; B.B. Fredholm, M.P. Abbracchio, G. Burnstock, J.W. Daly, T.K. Harden, K.A. Jacobson, P. Leff, M. Williams
Adenosine A1 receptors are present in almost all brain areas, with the highest levels in hippocampus, cerebral and cerebellar cortex, and certain thalamic nuclei. Only moderate levels are found in caudate-putamen and nucleus accumbens. The distribution of adenosine a1 receptors and 5'-nucleotidase in the brain of some commonly used experimental animals; J. Fastbom, A. Pazos, J.M. Palacios
Adenosine A2A receptors are found in the dopamine-rich regions of the brain: A2A receptor mRNA was colocalized with dopamine D2 receptors in enkephalin-expressing, medium-sized spiny neurons in the dorsal striatum, however neurons that express dopamine D1 receptors and Substance P and large aspiny cholinergic neurons do not express adenosine A2A receptor mRNA. Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain; Björn Johansson, Susanne Ahlberg, Ingeborg van der Ploeg, Stefan Brené, Nils Lindefors, Håkan Persson, Bertil B. Fredholm
Cellular effects of caffeine via A1 receptors
In hippocampal CA1 and CA3 neurons adenosine acting on A1 receptors has been shown to decrease calcium entry via N-type channels or affecting, directly, a calcium-sensitive member of the release machinery. Inhibition of quantal transmitter release in the absence of calcium influx by a G protein-linked adenosine receptor at hippocampal synapses; Kenneth P. Scholz, Richard J. Miller
Because increased levels of cyclic AMP in nerve endings are associated with an increase in transmitter release and because activation of adenosine A1 receptors is known to cause a decrease in cAMP formation it is conceivable that this may also be a mechanism of decreased transmitter release.
Adenosine also acts to decrease the rate of firing of central neurons. This effect appears to be quite general and is due to an activation of potassium channels via adenosine A1
receptors. The role and regulation of adenosine in the central nervous system; Thomas V. Dunwiddie, Susan A. Masino]^
Mesocortical cholinergic neurons are tonically inhibited by adenosine and caffeine consequently increases their firing rate. It was postulated that this effect is of importance in the electroencephalogram (EEG) arousal following caffeine ingestion. Adenosine Inhibition of Mesopontine Cholinergic Neurons: Implications for EEG Arousal; Donald G. Rainnie, Heinz C. R. Grunze, Robert W. McCarley, and Robert W. Greene
Is also known that caffeine increases the turnover of several monoamine neurotransmitters, including 5- hydroxytryptamine (5-HT) dopamine and noradrenaline. Because dopaminergic and noradrenergic neurons also are involved in arousal, there is ample neuropharmacological basis for assuming that central stimulatory effect of caffeine could be related to inhibition of adenosine A1 receptors.
Cellular effects of caffeine via A2 receptors
As noted above, A2A receptors are located preferentially in the subpopulation of the medium sized spiny GABAergic neurons that project to globus pallidus, in which they are colocalized with dopamine D2 receptor mRNA. These colocalized receptors have been shown to interact functionally. Thus, activation of A2A receptors has been shown to decrease the affinity of dopamine binding to D2 receptors. These interactions have a functional role in the intact striatum: dopamine acting on D2 receptors block the release of GABA in the globus pallidus, effect inhibited by adenosine, and so caffein acting as an antagonist on A2A receptors inhibit the release of GABA in the pallidus. This might explain the enhancing effects of caffeine on locomotor activity. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes; Ferre ́ S, von Euler G, Johansson B, Fredholm BB and Fuxe K
Actions of Caffeine on Brain Functions and Behavior
Caffeine macroscopic effects on the activity of the brain and on behaviour are mostly on motor functions, information processing, memory and sleep.
Effects on Motor Behaviour
The interaction between adenosine A2A and dopamine D2 receptors highlighted above could provide a mechanism for several actions of caffeine and some of its metabolites on dopaminergic activity. Thus, an inhibition of A2A receptors by caffeine would be expected to increase transmission via dopamine at D2 receptors in the striatum.
It is well known that the striatum is strongly involved in the regulation of motor behavior in animals and humans. Caffeine actions on these neurons enhance locomotion and movement. In both rats and mice the effect of caffeine on spontaneous locomotion is markedly biphasic. The threshold effect is 1 to 3 mg/kg and the peak effect is seen between 10 and 40 mg/kg. Locomotor Activity in Mice During Chronic Treatment With Caffeine and Withdrawal; Nikodijevic ̧ O, Jacobson KA and Daly JW
Caffeine can also induce rotation in animals with unilateral nigrostriatal lesions mimicking the the effects of dopamine receptor agonists, with a dose-dependant effect. This effect induced by caffeine is related to adenosine receptor blockade. On the mechanism by which methylxanthines enhance apomorphine-induced rotation behaviour in the rat; Fredholm BB, Herrera-Marschitz M, Jonzon B, Lindström K, Ungerstedt U
Effects on Mood
The effects of caffeine on mood have been studied in human subjects. Lower doses (20–200 mg) of caffeine are reliably associated with “positive” subjective effects. The subjects report that they feel energetic, imaginative, efficient, self-confident, and alert; they feel able to concentrate and are motivated to work but also have the desire to socialize. Caffeine : A Drug of Abuse?; Roland R. Griffiths and Geoffrey K. Mumford However, high doses of caffeine can induce a state of anxiety (with considerable differences in the anxiogenic dose between individuals). Drugs which induce anxiety: caffeine; Hughes R.N.
Effects on Information Processing and Memory
In humans Caffeine increases cortical activation, increases the rate at which information about the stimulus accumulates, increases selectivity with regard to further processing of the primary attribute, and speeds up motor processes. In rat brain counteract the depressive effects of adenosine on long term potentiation, a mechanism typically involved in memory formation.
The dose-response curve is U shaped: doses of 500 mg cause a decrease in performance although lower doses have positive effects. These effects follows the relationship between level of arousal and performance. In fact, individuals with a low level of arousal experience a beneficial effect, while in situations with a high level of stress caffeine consumption might be detrimental. Mood and performance effects of caffeine in relation to acute and chronic caffeine deprivation; Nicola J. Richardson, Peter J. Rogers, Nicola A. Elliman, Russell J. O'Dell
Effects on Sleep
Caffeine in doses corresponding to one cup of coffee taken at bedtime increases sleep latency and decreases the reported quality of sleep in parallel with small changes in the EEG pattern during sleep, especially in the non-REM deep sleep. It interferes with a modulatory mechanism in sleep regulation, not with a fundamental sleep regulatory brain circuit. Caffeine reduces low-frequency delta activity in the human sleep EEG; H.P. Landolt, D.J. Dijk, S.E. Gaus, A.A. Borbély
Adenosine might act as a signal to go to sleep, in fact adenosine receptors antagonists, in rodents, increased sleep and altered the EEG pattern in a dissimilar way than barbiturates. So caffeine might elicit its effects on sleep acting as an antagonist on these receptors. Role of adenosine in sleep in rats; Radulovacki M.
As noted above, caffeine has lots of beneficial effects on the activity of the brain. It is in fact widely consumed for its psycho-stimulant effects that results in incresed alertness, increased efficiency, increased motor activity and minor sleepiness. It also has beneficial effects on memory formation and on mood.