Adenosine plays an important role in linking the metabolic and excitatory functions of the central nervous system. Adenosine is not a neurotransmitter in the classical sense of the term, but rather a modulator of the activity of certain neurotransmitters. It has an inhibitory activity on two excitatory neurotransmitters, acetylcholine and glutamate.
The hypnotic effects of adenosine have been amply demonstrated. Stimulants such as caffeine or theophylline act as antagonists at the adenosine receptors. Adenosine facilitates deep slow sleep. There is mounting evidence for adenosine as a key chemical in the homeostatic process of sleep regulation. Indeed, the extracellular concentrations of adenosine gradually increase during waking and gradually decrease during sleep.
Adenosine may promote drowsiness by inhibiting the activity and release of neuro-transmitters from neurons that facilitate arousal. These inhibitory effects could be exerted on cholinergic and non-cholinergic neurons. The cholinergic basal forebrain is an important brain site in mediating the somnogenic effects of adenosine after sleep deprivation. The effects of adenosine at this site go through adenosine A1 receptors. One of the mechanisms by which adenosine induces sleep could be a blockage of inhibitory efferences on neurons in the ventrolateral preoptic nucleus.
The effects of adenosine on sleep could also be through interaction with GABA cells. In this sense, adenosine A2A receptors have been found on gabaergic cells.
Sleep changes with age. One explanation for this may be found in changes to adenosine receptors. This orientation was tested for the effects of caffeine, an adenosine A1 and A2A receptor antagonist, on the sleep of young, middle and high age rats, and it was shown that rats middle-aged and older were more sensitive to the arousing effects of caffeine than young-aged rats.
One wonders if the production of adenosine could not be reduced during waking, explaining the reduction of deep slow sleep and the fragmentation of sleep with age. On the contrary, it has been shown that older rats have higher levels of adenosine than those of young rats. A high production of adenosine in older animals may therefore reduce the sensitivity of adenosine receptors, thereby explaining the changes in sleep in the elderly.
Insomnia could be related to certain abnormalities in the adenosine system, which are responsible for a decrease in deep slow sleep and total sleep time. This orientation has been tested by the administration of caffeine in insomniacs and in control subjects, and it has been shown that after one night of total sleep deprivation and with administration of caffeine, insomniacs had a longer latency of sleep on the iterative sleep latency test that the subjects control.
The importance of adenosine deaminase in the duration and intensity of sleep in humans has recently been demonstrated.
Finally, it was demonstrated, by microdialysis of A1 and A2A receptor agonists / antagonists in the lateral preoptic area, that the effects transmitted by adenosine were dependent sites and receptors.
THESE MOLECULES THAT ACCUMULATE AND SLEEP US
It seems that two processes have to overlap properly in the body before one can fall asleep. The first is a so-called “circadian” rhythm, that is to say regulated over a period of 24 hours by our biological clock, and which orchestrates the cyclic secretion of several hormones including melatonin, involved in sleep. The second process is the accumulation of “hypnogenic” substances during the 16 hours of the day, substances which induce a desire to sleep which disappear only with sleep.
Falling asleep would therefore only be possible when, on the one hand, your biological clock has brought your body into a hormonal conformation favorable to sleep, and on the other hand that it has been a long time since you have slept.
One of these most studied hypnogenic factors is adenosine, a small molecule that acts as a neuromodulator in many brain synapses. For a very long time, natural adenosine receptor antagonists have been ingested by humans to keep them awake longer. Caffeine from coffee or theophylline from tea, which are two of these substances, are well known for their stimulating effect.
Schematic representation of an adenosine molecule
(green = carbon atom; blue = nitrogen atom;
red = oxygen atom; white = hydrogen atom;
pink: phosphorus atom)
It was in the early 1980s that the reason why so many people woke up coffee to wake up became obvious: caffeine, the psychoactive substance in coffee, prevents adenosine from attaching to certain neurons in the brain.
It was from this point that adenosine began to interest more and more neurobiologists working on sleep. Several animal experiments have possibly confirmed a certain role for adenosine in the sleep / wake cycle: blocking its action increases the level of alertness; injection of an adenosine agonist induces sleep; the concentration of adenosine naturally increases in certain areas of the brain during the day and decreases at night; this same concentration increases if the animal is forced to stay awake during the night; etc.
These experiments therefore show that adenosine, with serotonin and melatonin for example, is one of the molecules whose concentration in the brain influences the onset of sleep.
But how, exactly, does it influence it? During arousal, neural activity increases the level of adenosine. On the other hand, the effect that adenosine has on many neurons is inhibitory. And among the neurons thus inhibited by adenosine are those that are most active during sleep, the noradrenaline, acetylcholine and serotonin systems. For example, experiments have shown that when the level of adenosine in the basal telencephalon is artificially elevated, its neurons that project across the entire cortex produce less acetylcholine. This therefore results in slower cortical activity and drowsiness.
The synchronized brain activity characteristic of slow sleep will then be able to impose itself and, after a certain period of slow sleep, adenosine levels will start to decline. The activity of the systems responsible for the waking state will then be able to increase again, causing them to wake up and restart the cycle. This is, without a doubt, a very well oiled negative feedback (see cybernetic capsule on the left).