When I am stressed (and I'm stressed a lot of the time, as I bet a lot of you are as well), I turn to coffee. Not just to keep me going through the time when I need to get things done, but also for relaxation. For me, the smell and taste of coffee brings me thoughts of relaxing conversations with friends and other fun times.

But what if the memories weren't all the relaxing the caffeine was doing for me? What if the chronic caffeine consumption was keeping my stressful life at bay?

It's time to look at adenosine 2A receptors in the hippocampus. Don't worry, the coffee will be back.


Batalha, et al. "Adenosine A2A receptor blockade reverts hippocampal

stress-induced deficits and restores corticosterone circadian oscillation" Molecular Psychiatry, 2012.

First let's talk about stress. Specifically, childhood stress. In small doses, stress exposure can actually be good for you, but in large, or prolonged, doses, it's definitely not. There are effects immediately after stress, as well as long term ones. when you suffer strong stressors in development, you can end up with changes all the way into adulthood, from cognitive deficits to predisposition to psychiatric disorders.

Why is stress in development so important? During development, our brains are developing too, particularly our hippocampus. While the hippocampus is best known for its role in memory and spatial navigation, it's also extremely important in emotional responses. Neuronal growth in the hippocampus can come from enriched environments or chronic antidepressants, and death of those neurons can come from chronic stress. Chronic stress also disrupts the hypothalamic-pituitary-adrenal axis (the HPA axis) And that's just in adults! During development, animals are very susceptible to stress, and the hippocampus is still developing its connections. And we're still figuring out what changes occur during early life stress and how they relate to behaviors in adulthood.

In this case, the authors of this study were looking at adenosine 2A receptors. Adenosine is a neurotransmitter, a chemical messenger between neurons, that plays a role in promoting sleep as one of its functions. But the role of adenosine really relies on what receptors it hits, and where those receptors are. In the hippocampus, for example, adenosine 2A receptors can increase transmission of glutamate, another neurotransmitter, and can contribute to disorders and dysfunction. For example, high adenosine 2A receptors can be seen in response to acute stress, or in Alzheimer's. If adenosine 2A receptors in the hippocampus are altered in acute stress, and the hippocampus is altered by chronic stress in early life, does this mean that adenosine 2A receptors could have anything to do with chronic stress?

To find this out, the authors used a long-established early life stress model called maternal separation. Rat pups get separated from their mother for a period of time every day during development, and this can cause symptoms of chronic stress. You might think that there are poor sad baby rats calling for their mother and left alone and cold for days, but really, it's only for a three hour stint every day. Still, the animals grow up very differently from controls. They are more anxious and they show cognitive impairment in memory tests like the morris water maze.

But what's the role of the adenosine 2A receptor in all of this? The authors put a bunch of baby rats through maternal separation, and looked at them in adulthood. The rats showed signs of being chronically stressed.

(Figure 1A from the paper)

What you can see in the figure above is measures of mRNA of the glucocorticoid receptor (GR). This is one of the two receptors which responds to cortisol (corticosterone in rodents), the stress hormone. The GR is the most responsive to stressors, and you can see that it's been very affected in the stressed rats. The control rats are in black, and you can see in the stressed rats, every brain region they checked (hippocampus, cortex, or striatum), the GR mRNA (messenger RNA which is then translated to the protein receptor) is lower.

Why is this the case? Because the receptors are over stimulated.

(Figure 1E)

Above you can see the plasma corticosterone levels of the control (black bars) and stressed (white bars) rats. You can see that the stressed rats had much higher levels of corticosterone, a hormone released in response to stress. They may only have been stressed as babies, but they remain pretty stressed now.

Do adenosine 2A receptors have anything to do with this?

(Figure 4)

In the stressed rats (white bars), the adenosine 2A receptors were MUCH higher than in the control animals. This could mean that adenosine 2A receptors are important in how the animals respond to stress. To find out what role the receptors play, the authors gave an adenosine 2A receptor antagonist to the rats for a month, effectively blocking the receptors.

(Figure 3A)

What you can see above is a measure of anxiety behavior in rats, the elevated plus maze. Rats like dark, enclosed spaces, so they should like to spend time in the closed arms. But if a rat is curious enough, he'll explore the open arms of the maze as well. You can see that the stressed rats (white bars) are much more anxious than the control rats (black bars), spending far less time in the open arms of the maze than the controls. BUT when you give them the adenosine 2A antagonist (the light grey bar), they stop being anxious! The adenosine 2A receptor is playing a role in their anxiety.

(Figure 3D)

And not just anxiety! Here we have the data from the morris water maze. The morris water maze is a test of memory in rodents. The rats are placed in a big swim tank that is filled with milky water (or sometimes, just milk), so they can't see the bottom. They swim around until they find a hidden platform in one quadrant of the maze, where they can stand. After a bit of training, the rats get pretty good, and head straight for the platform.

...unless they don't. You can see that the stressed rats (white bars) spent less time in the quadrant with the platform during testing, they weren't as good at remembering where the platform was. But if you gave them an adenosine 2A antagonist (grey bars), they got better.

The adenosine 2A antagonist, in fact, normalized a lot of messed up things in the stressed rats. The stressed rats show less plasticity in their neuronal growth, the antagonist fixed it. It fixed levels of other receptors in the hippocampus. And finally it fixed the stress hormones themselves.

(Figure 5)

Above you can see two sets of corticosterone readings, from the morning and at night. Corticosterone has a circasian rhythm, it's low in the morning and high at night. But in the stressed rats (white bars) it was higher ALL the time.

Until you gave the adenosine 2A antagonist. When the authors blocked these receptors, they restored the rhythm of the corticoterone, it was now low in the morning (the light grey bar) and high at night.

So it looks like adenosine 2A receptors in the hippocampus are very important in the long term effects of stress. Chronic stress in development increased the 2A receptors in the hippocampus and produced a lot of biological and behavioral changes, but giving a 2A antagonist long-term could set the behaviors and biology right again.

What hit me at once about this paper was the phrase "adenosine 2A antagonist". There's a good reason for this, the most well known adenosine 2A antagonist is caffeine! So it makes me wonder if, in some situations, caffeine might be able to help combat the effects of developmental stress. I always knew drinking coffee was relaxing...

Of course, it's actually going to be far more complicated. Caffeine's interactions with adenosine 2A receptors are much more varied than another antagonist might be. So caffeine itself may not be the answer. But it DOES open up interesting ideas of new ways to treat chronic stress. Caffeine may not work (though who knows, it might), but could a specialty 2A antagonist help humans with messed up HPA activity? While I showed you high corticosterone in rats, humans with anxiety disorders and depression often have high cortisol levels (the matching human hormone), not to mention the symptoms of depression and anxiety. Could the 2A antagonist (or maybe a little caffeine) end up helping these symptoms in the long term? It seems a little odd, as caffeine in a single dose usually increases anxiety rather than the opposite. But it could be that adenosine 2A antagonists could make a different, maybe long term or in different doses. In the meantime, I'm taking it as just another reason to drink coffee.

Batalha, V., Pego, J., Fontinha, B., Costenla, A., Valadas, J., Baqi, Y., Radjainia, H., Müller, C., Sebastião, A., & Lopes, L. (2012). Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation Molecular Psychiatry, 18 (3), 320-331 DOI: 10.1038/mp.2012.8