Sleep chemistry and what makes us sleep has always fascinated me. Here we discuss the role of melatonin and adenosine.
This time I am writing an article on sleep or more specifically sleep chemistry. The famous author Ernest Hemingway once said, “I love sleep, my life has the tendency to fall apart when I’m awake.” There may be more truth in this statement than he ever realised!
A new study in ‘Nature Communications’ (by Zada et al) published this month discovered that broken DNA builds up in brain cells in the daytime and repair work reverses the damage only during sleep. In fact, one of the lead researchers suggested “I think this is one of the key reasons we need to sleep. An offline period gives us time to clean up everything for the next day, to give us a fresh start before we are busy with wakefulness again.”
Sleep is essential to all animals with a nervous system and prolonged sleep deprivation is not good for us. These thoughts revolved through my mind as I watched five couples rapidly transiting across countries and time zones in ‘Race Across the World’ on BBC2. This all looked particularly tiring and very bad news for DNA repair! The second episode required them to travel from Delphi (Greece) to Baku (Azerbaijan). This is a two-thousand-mile journey, out of Greece, across Türkiye and Georgia, and into Azerbaijan. The winners of this second leg achieved victory by employing the masochistic tactic of boarding a 16-hour overnight bus from Greece to Istanbul only to catch a second bus bound for Tbilisi in Georgia (a 1100-mile journey lasting in excess of 24 hours!). I remember only too well travelling those sorts of distances in the 1980s in South America and I share their pain.
However, you don’t need to undertake long distance bus journeys to feel tired. Ironically, I fell asleep watching all their endeavours after a day’s work at our clinic in Buxton. My question is… ‘what makes us fall asleep?’
The Role of Melatonin in Sleep Chemistry
As some of us already know, in terms of neuroscience, one of the circulating neural messengers involved in sleep chemistry is the hormone melatonin. It is naturally synthesised from the amino acid tryptophan (via synthesis of serotonin). Interestingly many animals use melatonin production to regulate their seasonal clock. For them the profile of melatonin synthesis and secretion is influenced by the duration of the night during summer and winter. This serves as a biological clock for reproduction, behaviour, coat growth and camouflage colouring. Melatonin is also related to the mechanism by which some amphibians and reptiles change the colour of their skin. We can do the same thing when we are exposed to sunlight, but much more slowly! Very slowly in Buxton!
In humans at the end of day, as dusk approaches and daylight fades, a nucleus in the brain (the suprachiasmatic nucleus) instructs your pineal gland to begin releasing melatonin. Basically, melatonin merely informs us that that sleep is imminent. Melatonin does not specifically and in isolation induce sleep, this is a common misconception. Essentially it really acts as a ‘starting gun’ for the beginning of the race. So, what happens next?
The Role of Adenosine in Sleep Chemistry
One of the other key factors in sleep chenistry is the molecule adenosine. The cumulative effect of the increasing presence of adenosine after 12-14 hours of wakefulness will give us the irresistible urge to sleep.
Adenosine is produced from the degradation of adenosine triphosphate (ATP). ATP is important in the generation of energy. ATP is constantly formed and broken down as it participates in biological reactions and it is central to the health and growth of all life. Without it, cells could not transfer energy from one location to another, making it impossible for organisms to grow and reproduce.
When you are awake it makes perfect sense that neurons and glial cells in your brain utilise huge amounts of ATP. Adenosine levels therefore increase as a bi-product of this activity and this imposes what we call ‘sleep pressure’. A typical healthy human brain has roughly 100 billion neurons and there are about ten times more glial cells than neurons.
Twenty per cent of the energy we produce services our brain function, so this involves a lot of ATP. Adenosine, as it accumulates, progressively binds to receptor sites in the brain and one of the triggering effects of this docking process is the progressive urge to sleep after 12-16 hours of wakefulness (hence the term sleep pressure). As this process escalates there is also a corresponding depletion in your ATP reserves and, as you sleep your brain begins restocking its energy bank. During sleep an enzyme called adenosine deaminase (or ADA) will metabolise adenosine to levels that are more appropriate for wakefulness.
How does Coffee Disrupt Sleep?
A phenomenon that is worth mentioning is the effect of coffee. Caffeine directly opposes the effect of sleep pressure. Caffeine competes with adenosine for the same receptor sites and blocks the signal that makes you feel sleepy. It acts as an adenosine-receptor antagonist.
Coffee has a half-life of 5-7 hours (half-life is the time it takes your body to remove 50% of a drug’s concentration) during which time it occupies these receptors negating the effect of adenosine. The caffeine of course will slowly be broken by another enzyme from the liver and the receptor sites will eventually be made available once again. This whole process explains why coffee perks us up and why we prize it!!
Under normal circumstances, with no caffeine, it takes about eight hours for the adenosine purge to be completed in an adult brain. This then combines with our internal body clock. The presence of daylight effectively puts a brake on the production of melatonin and encourages us to wake up and the whole circadian rhythm begins once again.
