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Caffeine: where are its sites of action in the human brain?

Caffeine is the most commonly consumed psychoactive substance worldwide and an active ingredient in innumerable beverages and foods. Its neurobiological effects comprise mainly stimulatory actions on alertness, attention, cognitive performance, and cerebral perfusion. It reduces sleepiness, prolongs sleep latency, and enhances wake periods after sleep onset. The biological actions of caffeine are generally assigned to its antagonizing effects at cerebral adenosine receptors. However, the precise localization of these sites of action is still poorly understood.

 We studied the sites of action of caffeine using PET. Volunteers received an intravenous injection of a radioactive marker (radioligand). Subsequently, different doses of caffeine were applied intravenously. The doses were in range of 2 to 4 cups of coffee which corresponds to commonly consumed amounts of caffeine. 

PET imaging revealed that the radioligand bound selectively to a specific type of cerebral receptors, the A1adenosine receptor. Caffeine was able to displace the radioligand from its binding site and to block the adenosine receptors. An amount of caffeine that is usually consumed during a day (four to five cups of coffee) was sufficient to occupy 50% of adenosine receptors. As the action of adenosine is inhibitory, the blockade of these receptors by caffeine seems to result in a disinhibition, i.e. an activation of neurons.

Verteilungsvolumen eines Probanden nach der Gabe von Koffein

Fig. 1: Representative parametric images of the total distribution volume of a single subject at baseline and after 4.1 mg/kg bodyweight of caffeine. The upper row shows the corresponding anatomic MRI with an overlay of the regions of interest which were used for analysis.

Dosisabhängige Verdrängung von [18F]CPFPX durch Koffein im frontalen Kortex

Fig. 2: Dose-dependent displacement of [18F]CPFPX by caffeine in the frontal cortex. Total volume of distribution (VT) is plotted versus time for four subjects that received different doses of caffeine or vehicle at 90 to 100 min.

Zusammenhang zwischen der Konzentration von Koffein im Blutplasma

Fig. 3: Relationship between caffeine plasma concentration and A1 adenosine receptor occupancy (n = 16) estimated for all regions using the slope of the occupancy (Lassen) plot. The line represents the corresponding fit used to determine 50 % occupancy.

The study has been published in:

Elmenhorst D, Meyer PT, Matusch A, Winz OH, Bauer A (2012). Caffeine Occupancy of Human Cerebral A1-Adenosine Receptors: In Vivo Quantification with [18F]CPFPX and PET. J Nucl Med. 53(11):1723-1729.