From The Vault: A coffee a day keeps the adenosine at bay

It’s fair to say that for most of us the day doesn’t truly begin until we can feel the warm lick of caffeine coursing through our veins. Be it an espresso, flat white, latte or low-fat, soy, double-shot, moccacino. Whatever your poison very little in our lives is ever achieved before that first cup of black magic has passed our lips.

However despite our love affair with this bitter alkaloid, the exact manner in which caffeine interacts with our brains has been largely misunderstood. That is until now.

Not your average stimulant

It should be said right from the start that caffeine is not your average stimulant. Unlike more illicit uppers such as amphetamines and MDMA which exert their effects by increasing noradrenaline levels, caffeine exerts its effects by blocking, or antagonising, adenosine receptors. When our brains switch on each morning and the neurons begin firing away they also begin to produce the neuronal by-product, Adenosine. Throughout the day, the neurons keep firing, adenosine levels keep rising and adenosine receptors throughout the CNS begin to monitor the action. Once a certain level of adenosine has been reached the receptors in your brain and spinal cord tell you that perhaps it’s time to go to sleep. Or at least close your eyes for just a short while.

Enter caffeine. Whether from your coffee, your tea, your chocolate or your guarana, it flows into your body, heading straight for your adenosine receptors, or more specifically your adenylyl cyclase-modulating g protein-coupled A1 receptors. Once at the receptor it binds with great efficiency, due to its similarities with adenosine. However its differences mean that despite binding, caffeine doesn’t actually activate the receptor and so no sleep signal is sent to the brain. So with caffeine acting like “a  block of wood under one of the brain’s primary brake pedals“, the brain’s natural stimulants, dopamine and glutamate, are left to do what they do best.

Of course we each have differing amounts of these natural stimulants floating around our heads at any given moment and so the effect of a coffee is somewhat variable from person to person and at different times of the day. The take home message is that coffee doesn’t act to wake you up, but rather it acts to stop you from going to sleep. Which isn’t quite the same thing, when you really think about it.

Posterior and inferior cornua of left ventricle exposed from the side

Next stop Hippo campus

Those of us who are regular partakers of the international psychoactive stimulant of choice know that coffee is so much more than just a drowse defying beverage. It is an elixir which increases our acuity and alertness. And it does this by acting on the hippocampus. Previous research has suggested that the inhibitory action of caffeine on the A1 receptors within the hippocampus, or more specifically the CA1 region, acts to evoke an enhancement in signal transmission between neurons, known as long-term potentiation (LTP). However a more recent study investigating the role of caffeine on the less well defined CA2 region, which just happens to contain the highest concentration of adenosine receptors, suggests that the role caffeine plays in our mental acuity might not be that simple.

The researchers found that excitatory post-synaptic currents were increased in the CA2 region, but not the CA1 region, of juvenile rats fed with caffeine for up to an hour after the caffeine was consumed. Furthermore when caffeine was added directly to naive slices of rat hippocampus, the increase in CA2 excitatory post-synaptic currents was measurable for up to three hours after the caffeine was applied. That is to say that caffeine was found to induce long-term potentiation through the CA2 region.

However the real interest of the article lies not in the fact that LTP was induced but rather in the manner in which caffeine acted to induce it. Within the CA1 region the induction of LTP is dependent on the activation of N-Methyl-D-aspartate, or NMDA, receptors and the consequential calcium dependent signalling pathway. As a result the addition of either an NMDA receptor antagonist or a calcium signalling inhibitor will act to prevent LTP in the CA1 region. However when added to the CA2 region neither the NMDA receptor antagonist nor the calcium signalling inhibitor had any effect on LTP. Instead LTP induction was found to involve the activation of the aforementioned adenylyl cyclase-modulating g protein which the A1 receptors are bound.

The results of this study hint towards ‘a more complex signalling mechanism governing the consolidation of‘ LTP and helps to shed some light on the largely unknown role of the CA2 in normal brain function. Perhaps most importantly though is that it gives those of us addicted to our daily grind another excuse for that extra cup.


  • Simons, S., Caruana, D., Zhao, M., & Dudek, S. (2011). Caffeine-induced synaptic potentiation in hippocampal CA2 neurons Nature Neuroscience, 15 (1), 23-25 DOI: 10.1038/nn.2962

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