Caffeine - Pharmacology - Mechanism of Action

Mechanism of Action

Adenosine acts as an inhibitor neurotransmitter that suppresses activity in the central nervous system. Consumption of caffeine antagonizes adenosine and increases activity in neurotransmission including acetylcholine, epinephrine, dopamine, serotonin, norepinephrine and glutamate. There has also been conclusive evidence that caffeine inhibits acetylcholinesterase, an enzyme that breaks down acetylcholine; therefore the duration of acetylcholine is increased in the nicotinic and muscarinic receptors in the central nervous system.

Because caffeine is both water-soluble and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.

Adenosine is found in every part of the body, because it plays a role in the fundamental adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors located on vascular smooth muscle. Brain adenosine levels are increased by various types of metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that adenosine functions as a synaptically released neurotransmitter in some parts of the brain; however, stress-related adenosine increases appear to be produced mainly by extracellular metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a voltage-controlled manner, but the possibility of such a mechanism has not been ruled out fully.

Several classes of adenosine receptors have been described, with different anatomical distributions. A₁ receptors are widely distributed, and act to inhibit calcium uptake. A_2A receptors are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower densities. There is evidence that A _2A receptors interact with the dopamine system, which is involved in reward and arousal. (A_2A receptors can also be found on arterial walls and blood cell membranes.)

Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically involved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation of adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the effects may be mediated both by inhibition of wake-promoting neurons via A₁ receptors, and activation of sleep-promoting neurons via indirect effects on A_2A receptors. More recent studies have provided additional evidence for the importance of A_2A, but not A₁, receptors.

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine. In the classic, or metabolic theory, caffeine may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or intramuscular triglycerides by increasing circulating epinephrine levels. The increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby enhancing endurance performance. In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit the muscles for exercise.