Why caffeine jacks you up

25 July 2011 by David Johnson, posted in Neuroscience

Have you ever wondered why, and exactly where in the brain, coffee (or any caffeinated product, for that matter) is able to exert its arousing effects? Well, wonder no longer, because an international team of researchers from Japan, China and the US, have located the primary neurons upon which caffeine works its magic (Lazarus 2011).

It was previously known that caffeine wakes you up through inhibiting activity at adenosine A2a receptors (adenosine is an inhibitory neuromodulator involved in regulating the sleep-wake cycle). However, it was not known exactly where in the brain the receptors that exerted this effect are located.

How did they do it?
The researchers utilized a method whereby the gene that codes for A2a receptors (A2aRs) is marked such that they can be deleted, but only in a specific regions of the brain. Using a rat model, the team utilized these gene deletion strategies and found that when they knocked out A2aRs in the shell of the nucleus accumbens, rats no longer experienced the arousing effects of caffeine.

How does this work?
Adenosine activates A2a receptors in the nucleus accumbens shell, activation of which receptors inhibit the arousal system. That is, the more adenosine activation there is, the sleepier an organism becomes. Caffeine, which binds to these same receptors and blocks adenosine from exerting its activity there, essentially disinhibits the arousal system, promoting wakefulness. (Amazingly, based on similarities between the brains of mice and men, the area of the human brain in which caffeine acts to counteract fatigue is approximately the size of a pea.)

What does this mean in practical terms? (or, in other words, why should we find this so cool?)

Well, for one, it gives us a more specific mechanistic explanation for the arousing effects of caffeine. It says that in order for caffeine to work, it not only has to be effective as an A2aR antagonist, but that excitatory A2aRs on nucleus accumbens shell neurons must be tonically activated by endogenous adenosine. This is especially important in consideration of individual differences in the subjective effects of caffeine.

What if A2aRs are more densely packed in the shell of your nucleus accumbens than in mine? Might you be more sensitive to the effects of caffeine than me? That certainly seems likely. And the reason that one person might over or underexpress these receptors vs. another seems to be related to variation in the gene that produces those receptors (the gene knocked out in the rat study described above). In fact, we’ve already have evidence that this is the case. Past studies have shown genetic variations in genes coding for A2aRs were associated with greater sensitivity to caffeine and sleep impairment (Retey 2007), and greater anxiety after caffeine (Childs 2008). This study refines the existing model and should inspire, and lead to more accurate interpretation of, future genetics studies.*

*Other significant genes that underly individual differences in the subjective effects of caffeine include CYP1A2, or cytochrome enzyme P-450 1A2, which is associated with caffeine metabolism, and those coding for dopamine D2 receptors.

Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, Winsky-Sommerer R, Semba K, Fredholm BB, Boison D, Hayaishi O, Urade Y, & Chen JF (2011). Arousal Effect of Caffeine Depends on Adenosine A2A Receptors in the Shell of the Nucleus Accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (27), 10067-10075 PMID: 21734299

Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 33:2791- 2800

Retey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP (2007) A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther. 81:692-698


6 Responses to “Why caffeine jacks you up”

  1. Laura Wheeler Reply | Permalink

    Thanks for your thoughts, it is remarkable what we can learn from genetic studies.  


    Past studies have shown genetic variations in genes coding for A2aRs were associated with greater sensitivity to caffeine and sleep impairment 

    I find this statement extremely interesting – caffeine sensitivity can be linked to sleep impairment. Does this mean that people who are more sensitive to caffeine (who are likely to have more A2aRs) are likely to suffer with other conditions like depression?

  2. David Johnson Reply | Permalink

    hey laura – Good question! There is some work out there showing links between adenosine and depression. One paper I skimmed through showed that genetical elimination and antagonism of A2aRs effectively reversed behavioral despair in mice. The authors hypothesized that this was mediated through dopaminergic transmission and suggested, therefore, that a clear cut antidepressant effect couldn’t be attribute to A2aR antognists ( such as caffeine). But it may be the case that adenosine 2a receptors are indirectly linked to depression (probably lots of work out there and I didn’t do a thorough search…)

  3. David Colquhoun Reply | Permalink

    This is very ingenious work, but it doesn’t measure sleep.

    It’s always struck me as interesting that in Germany, most people seem to believe that if you drink coffee at any time after midday. you won’t sleep. In the UK many people will have coffee after dinner and sleep perfectly well.

    Personally, I find that it I wake in the middle of the night (a condition that can be brought on when I’ve encountered some particularly perfidious management bollocks) a good cup if hot strong coffee gets me back to sleep quite quickly.

    The great problems for people who try to link cellular actions to behaviour are (a) the use of surrogate outcomes and (b) species variation.



  4. David Johnson Reply | Permalink

    David – very true. It seems to be one of the top bits of advice for those with problems sleeping, "no coffee after 6 PM (or thereabouts)…" I experience the same thing as you describe – waking up too early in the AM, I often have a cup of coffee and then immediately fall back down for a very restful couple hours more sleep. Of course, the rats in the above study (and most studies of caffeine intake) aren’t  chronic users, but, rather, novices. 

    It’s certainly paradoxical that coffee/caffeine can exert such contrary effects in some users…


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