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Sleepiness is one of
the best known symptoms of infectious diseases. Hence one
might hypothesize some relationship between the regulation
of sleep and the body’s immune response to infection.
Some scientists believe that certain hypnogenic peptides
might cause fevers and mobilize the body’s immune response.
For example, cytokines, whose production
is stimulated by infections, may cause an increase in sleep
and thus help to increase the body’s immune defences.
Interleukin-1 is an
example of these peptides that simultaneously stimulate the
immune system and promote sleep. This peptide is synthesized
in the glial
cells of the brain and in the macrophages that remove
foreign bodies from the organism.
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MOLECULES THAT BUILD
UP AND MAKE YOU SLEEP |
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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. |
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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. |
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