MOLECULES THAT BUILD UP AND MAKE YOU SLEEP

The onset of sleep is triggered not only by your body’s biological clock, which regulates the cyclical secretion of hormones determining the best time to go to sleep, but also by the cumulative effect of hypnogenic molecules that build up in the body while you are awake.

The molecule adenosine has a number of characteristics that make it an ideal candidate to act as one of these hypnogenic substances: its concentration in the brain is higher during waking periods than during sleep and increases during extended periods of wakefulness; moreover, administering adenosine or its agonists to experimental subjects makes them sleepy.

Adenosine is produced by the degradation of adenosine triphosphate (ATP), the molecule that serves as the “energy currency” for the body’s various cellular functions. The amount of adenosine produced in the brain thus reflects the activity level of its neurons and glial cells. The brain’s intense activity during periods of wakefulness consumes large amounts of ATP and hence causes adenosine to accumulate.

The accumulation of adenosine during waking periods is thus associated with the depletion of the ATP reserves stored as glycogen in the brain. The increased adenosine levels trigger non-REM sleep, during which the brain is less active, thus placing it in a recovery phase that is absolutely essential—among other things, to let it rebuild its stores of glycogen. 

Because adenosine is continuously metabolized by the enzyme adenosine desaminase, the decline in adenosine production during sleep quickly causes a general decline in adenosine concentrations in the brain, eventually producing conditions more favourable to awakening.

Some interesting experimental results have been obtained when rats were injected with adenosine agonists that are not broken down by adenosine desaminase. These substances increased the amount of non-REM sleep, but decreased the amount of REM sleep, during which the brain is very active. But because REM sleep normally represents only 15% of the time that rats are asleep, these substances also significantly increased the total amount of time that the rats slept.

Similar results were also obtained with the administration of an adenosine desaminase inhibitor, which reduced the efficiency with which adenosine was metabolized and hence increased its concentration in the brain.

One of the first explanations proposed for the mechanisms by which adenosine exerts its hypnogenic effect was as follows. The binding of adenosine molecules to their receptors inhibits the enzyme adenylate cyclase, thus suppressing the inflow of calcium ions into the presynaptic terminals. And because this inflow normally promotes the release of neurotransmitters, smaller amounts of neurotransmitters would then be secreted by many neurons associated with wakefulness, such as those in the basal telencephalon. And that is how adenosine would exert its hypnogenic effect.

But what about those parts of the brain that were known to contain neurons whose stimulation promotes sleep, such as the preoptic anterior hypothalamus? Researchers soon found that injecting microscopic amounts of adenosine into these parts of the brain promoted sleep too. But according to the hypothesis described in the preceding paragraph, this result was paradoxical: reducing the activity of neurons that promote sleep should have promoted wakefulness instead.

What these researchers had failed to consider was the tremendously complex interplay of the various subtypes of adenosine receptors, which often have opposing effects. Subsequent research has shown that there are at least two different subtypes of adenosine receptors, with opposite effects: A1 receptors, which are inhibitory, and A2A receptors, which are excitatory. That is why adenosine can simultaneously have inhibitory effects via the A1 receptors on neurons that are active during wakefulness, such as those of the basal telencephalon, and excitatory effects via the A2A receptors in brain areas where neuronal activity encourages sleep.

That said, some in vitro experiments have also shown that adenosine may act presynaptically by inhibiting some inhibitory GABAergic inputs, possibly via the A1 adenosine receptors. In this way, adenosine might, for example, disinhibit some neurons in the preoptic anterior hypothalamus, thus further encouraging sleep. Yet another example of the immensely complex potential combinations of effects on the synapses of the brain.