Sleep Homeostasis: Sleep deprivation increases A1 adenosine receptor density

Human beings spend a considerable amount of our life sleeping. The function of this physiologic phenomenon and its regulatory processes are mostly unknown. We use molecular imaging to investigate the underlying neurochemical processes in the human brain which are involved with sleepiness and sleep.

We are in particular interested in the function of adenosine, a ubiquitous nucleoside which is considered to be an extracellular modulator of cellular activity. Its overall action is inhibitory and it influences neurotransmitter release. Caffeine, the worldwide most consumed psychoactive drug, exerts its alerting function by blocking adenosine receptors.

It is hypothesized that adenosine induces sleep, especially after a period of prolonged wakefulness. This process is partly reversible by the intake of caffeine which blocks adenosine receptors.

With prolonged wakefulness brain adenosine levels rise, while sleep brings adenosine levels back to normal. This observation lead to the conclusion that adenosine is a "sleep factor".

The sleep inducing effects of adenosine seem to be mediated by activating A₁ adenosine receptors which are ubiquitously expressed in the human brain.

The research group of R.W. McCarley, Harvard Medical School, was able to show that A₁AR mRNA is upregulated after 6h of sleep deprivation. In cooperation with this group we showed that A₁AR receptor density is also upregulated in both a basal forebrain region and with certain latency several cortical regions.

Fig. 1: Relative differences of two sleep deprivation conditions in comparison to a circadian control group.

Comparable PET experiments in healthy human subjects showed a significantly higher density of A₁AR after one night of sleep deprivation.

Fig. 2: Distribution volume and binding potential of A1 adenosine receptors in the temporal cortex of 10 subjects at baseline and 12 subjects after sleep deprivation. (A) Absolute values; (B) Scatterplots of intraindividual changes.

Fig. 3: Mean parametric images of A1 adenosine receptor binding potential before (B) and after sleep deprivation (C) and corresponding MRI (A).