Free adenosine is, as you have just learned, produced in your cells via the processes involved with energy production (as you may have guessed, it can also be produced by the breakdown of RNA). As such, the amount of adenosine produced within a cell is directly proportionate to the amount of work that the cell has done. This includes neurons and the closely associated cells also found in your brain, glial cells. As you have learned, your brain is an obligate glucose user and also a highly energy expensive mass.
If you look back to module 1 you will see that it uses more calories per hour, per pound, than almost any other tissue which means that a lot of ATP is being broken down during the day, especially if that day requires a great deal of mental work.
Adenosine is readily broken down to adenine and free ribose under normal conditions by the enzyme adenosine desaminase, but during wakefulness the breakdown of glycogen and glucose in the brain, therefore the usage of ATP far outreaches this and adenosine levels gradually build-up during wakefulness. Adenosine concentration within the neuronal cytoplasm increases, meaning that a concentration gradient starts to occur and the adenosine eventually crosses the membrane barrier and enters the extracellular space within the brain.
The adenosine can bind to neuronal synapses and adenosine receptors. There are a number of different ways in which this induces sleep, including:
Injecting exceedingly small amounts of adenosine into the brain of rats induces sleep, meaning that we can safely postulate that adenosine is indeed involved directly with sleep onset. Interestingly, one of the area’s most strongly associated with adenosine build up during the day is, as you might expect, the frontal cortex which is the region involved with complex cognitive tasks. This is why you feel extremely tired after hard study or learning, and why you sleep so deeply after these activities.
During non-REM sleep (especially stage 3 sleep), brain activity is heavily reduced meaning that adenosine clearance is significantly higher than production, and so you wake refreshed. During REM sleep you use a lot of ATP within your brain for the activity associated with this stage to occur but because this stage is relatively short, you wake refreshed after a long sleep. This is why incidentally, we mentioned that REM sleep deprivation does not seem to create the feeling of fatigue that inhibition of stage 3 sleep does.
It follows that adenosine build up is not something that will necessarily go away over time, nor is it something that will be reduced by one night of good sleep if this follows a period of deprivation. One study took two groups of participants – 1 group had two nights of 8 hour sleep while the other had a night with 2 hours of sleep and a night with 8 hours of sleep – though the second group slept well during the recovery sleep, they still displayed cognitive difficulties during a prescribed task on day 3. This indicates what should now be somewhat obvious, the build-up of adenosine in neuronal synapses is cumulative and therefore regular good sleep rather than the usual pattern of midweek poor sleep and weekend lie ins is a far more preferable approach.
As a final note, this is the primary mechanism by which caffeine exerts is effects alongside some others, including interaction with GABA receptors and enzymes involved with the breakdown of a molecule known as cAMP (that, in the brain, has involvement in the production of noradrenaline and norepinephrine amongst others, therefore raising heart rate and alertness). Caffeine effectively blocks adenosine receptors and therefore reduces adenosine’s ability to make you feel fatigued for a certain period of time, and in a very effective manner. Not only this, because some of the areas affected by adenosine are typically related to dopamine this can create a mood-boosting effect. This is not perfect, however.
Firstly, habitual caffeine intake does not remove adenosine from the brain, rather it prevents its binding to receptors. Once caffeine is metabolised and becomes inactive the adenosine is able to re-bind and fatigue sets back in. Caffeine consumption can therefore ‘mask’ a sleep debt but this is only temporary. As you have seen, reducing fatigue is not the only function of proper sleep and therefore using caffeine to mediate this behaviour can have far reaching affects. Moreover, chronic and habitual caffeine intake can result in an up-regulation of the adenosine system, meaning that over time you need more caffeine to have the same affect and, of course, upon cessation the symptoms of fatigue come on much more quickly.
Fortunately, individuals will adjust to a lower caffeine intake after a few weeks but this period can be uncomfortable, creating headaches amongst other things. Because of the ability of caffeine to mask a sleep debt and improve your mood by stimulating dopaminergic activity, it can be considered to be somewhat addictive and it is possible to fall victim to caffeine dependence syndrome. This will be mentioned to some degree later in this module but for now the take home is that, although caffeine can have obvious benefits, those benefits are not without side effects and habitual high intakes should possibly be avoided.
So far, we have discussed the role and mechanism of sleep, but how much do we need, and what happens when we don’t get enough?