Caffeine blocks adenosine receptors, thereby reducing the effect of adenaline.

It seems plausible to me, that blocking adenosine receptors should (perhaps ironically) increase the rate of adenosine buildup. For example because the body directly responds to a lower measured adenosine level by increasing adenosine production. or alternatively because coffee causes people to be more active, and this heightened activity may cause increased adenosine buildup.

Is my hypothesis correct?

  • Did you mean adenosine?
    – Carey Gregory
    Commented May 15, 2018 at 13:58
  • @careyGregory, woops, yes i meant adenosine.
    – user56834
    Commented May 15, 2018 at 17:04
  • I think your theory probably is basically correct. I'll wait another day or two before answering if no one else does.
    – Carey Gregory
    Commented May 16, 2018 at 4:15

1 Answer 1


Your question demonstrates a key understanding of homeostatic mechanisms: in many cases, long-term pharmaceutical modulation leads to compensatory changes that blunt the effects of the modulation. This can lead to rebound effects and sometimes physical/physiological dependence.

Your hypothesis is good, however, you have the mechanism wrong in this case. Blocking adenosine receptors tends to increase the expression of receptors, especially the adenosine A1 receptor, rather than the production of the agonist adenosine. Interestingly, this seems to be regulated not by increased transcription (mRNA production) but instead by later mechanisms (Johansson et al. 1993).

Receptor expression changes rather than agonist production changes tends to be a general rule for similar circumstances, though there are certainly exceptions as well. Altering receptor levels is a more reliable homeostatic mechanism, because often a given agonist acts on many different receptors with different affinities. It is also the cells expressing the receptors that have the most direct way to assay the level of receptor activation. In order to change agonist production levels, you would need a communication mechanism where the receptor cells signal back to the agonist producing cells, whereas receptor expression can be controlled all within the receptor cells.


Fredholm, B. B. (1982). Adenosine actions and adenosine receptors after 1 week treatment with caffeine. Acta Physiologica, 115(2), 283-286.

Johansson, B., Ahlberg, S., van der Ploeg, I., Brené, S., Lindefors, N., Persson, H., & Fredholm, B. B. (1993). Effect of long term caffeine treatment on A 1 and A 2 adenosine receptor binding and on mRNA levels in rat brain. Naunyn-Schmiedeberg's archives of pharmacology, 347(4), 407-414.

Ramkumar, V., Bumgarner, J. R., Jacobson, K. A., & Stiles, G. L. (1988). Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion. The Journal of clinical investigation, 82(1), 242-247.

Svenningsson, P., Nomikos, G. G., & Fredholm, B. B. (1999). The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. Journal of Neuroscience, 19(10), 4011-4022.

  • thank you. I was wondering whetheer there is even an direct effect on adenosine on the day you drink coffee (i..e. a short term effect). It seems that this is not the case, if the only channel is an increase in receptors. Couldn't there also be a more direct, short term effect?
    – user56834
    Commented May 16, 2018 at 18:38
  • 1
    @Programmer2134 I'm not aware of any and searched looking for one. I wouldn't expect receptors to be modulated on the timescale of a single day of coffee either. One possibility you might see in a research setting is that adenosine levels would end up higher before sleep began than normal, due to reduced drowsiness, but that's not really an adaptive increase in adenosine but rather a change in sleep behavior.
    – Bryan Krause
    Commented May 16, 2018 at 18:54
  • "due to reduced drowsiness", do you mean that a reduce in drowsiness causes increased rate of adenosine production (because thats precisely the mechanism I'm interested in), or do you mean that reduced drowsiness causes people to sleep at a later time, so that there has been more time for adenosine buildup?
    – user56834
    Commented May 17, 2018 at 6:31
  • I asked a followup question here: health.stackexchange.com/q/16310/6492
    – user56834
    Commented May 17, 2018 at 6:40
  • @Programmer2134 I actually had rodent studies in mind, but I meant "sleep at a later time, so that there has been more time for adenosine buildup"
    – Bryan Krause
    Commented May 17, 2018 at 15:53

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