We humans do love our stimulants. The most widely used one is caffeine, used the world over to make us just that much more awake and productive (in theory). But caffeine isn't like other things that we classify as stimulants, such as cocaine or amphetamine. Cocaine and amphetamine are thought to have their addictive potential and to produce their "high" by increasing levels of the neurotransmitter dopamine in reward related areas of your brain like the basal ganglia. But caffeine has long been thought to be different. It has negligible effects on dopamine, and it simply doesn't have the addictive potential of drugs like cocaine. While you can certainly become tolerant to caffeine, and you can certainly really want your daily dose, it doesn't present the powerful, all consuming craving associated with drugs like the classic psychostimulants. Instead, caffeine has its direct actions on the receptors for the chemical adenosine. Adenosine normally hits receptors (2A is the important one for today) and promotes sleepiness. Caffeine, however, is an adenosine receptor ANTAGONIST, which means that it hits those same receptors in place of adenosine, and promotes wakefulness instead.

But where are these receptors, and how are they working? It turns out the stimulant effects of caffeine, despite their activity at adenosine receptors, may be closer to dopamine than we first thought.


Lazarus et al. "Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens" J. Neuroscience, 2011.

A chemical is only as good as its receptor, and that receptor is only as good as where it's located, where those neurons are going, and what they connect to. In this case, we know that 2A Adenosine receptors are very densely located in the basal ganglia, an area of the brain known for its role in things like locomotor activity, arousal (which may be awake, but may also mean alert to stimuli), and responses to rewarding stimuli such as drugs of abuse.


The basal ganglia is also a center for dopaminergic activity, which plays a big role in locomotor activity and drug responses. Adenosine 2A receptors are often located very near dopamine receptors, does this have anything to do with the ability of caffeine to promote wakefulness?

To investigate this question, the authors of this paper developed a special strain of mouse. This strain of mouse had the adenosine 2A receptor specifically knocked out, but ONLY in the basal ganglia.

Here you can see a slice through the mouse brain. The circled area is the nucleus accumbens, part of the basal ganglia, which they have stained for adenosine 2A receptors. The wildtype shows normal receptor expression, while the Knockout mouse here draws a blank.

They used these mice to test the effects of caffeine. And while normal mice showed increased wakefulness (as measured by EEG) and locomotor activity in the presence of increasing doses of caffeine, the knockout mice were immune. Caffeine just didn't affect them at all.

In fact, the effects (or rather, lack of effect) of caffeine in mice that had adenosine 2A knockouts ONLY in the basal ganglia were similar to mice with adenosine 2A receptors knocked out all over the brain, which suggests that the adenosine 2A receptors IN the basal ganglia are the ones more important for the response. But it doesn't PROVE it. After all, these mice had had their adenosine 2A receptors knocked down in the basal ganglia for their entire lives, and this could affect how they developed, affecting in turn how they responded to caffeine as adults.

So the authors injected a virus into the brains of normal mice, which carried a conditional knockout gene for adenosine 2A, in this case which prevented the normal expression of the gene. They injected it into the basal ganglia (mouse brains are very small and you can't get much more specific), and tested the new knockouts with caffeine. Again, the effects of caffeine were decreased, but not the response to other drugs, like modafanil, which target other receptors. The deletion of adenosine 2A receptors affected only the caffeine response.

But again, mice are small. The basal ganglia has many parts to it, how do we know which is responsible? to look at this, the authors used rats (with much bigger brains), and used a viral vector this time to knockdown the adenosine 2A receptor in one part of the basal ganglia, the nucleus accumbens. And the rats showed no response to caffeine either. This effect was specific to the nucleus accumbens, when the scientists tried injecting the virus into other regions of the basal ganglia, they didn't get any differences.

So it looks like the adenosine 2A receptors in the nucleus accumbens may be responsible for the wakefulness effects of caffeine. Right now the authors hypothesize that, when caffeine hits the adenosine 2A receptors in the nucleus accumbens, this inhibits other neurons in that area, particularly those that normally release GABA. These GABA neurons project to arousal and sleep related centers of the brain, like the hypothalamus and the locus coerulus, so when they are inhibited, they could cause increased wakefulness by this pathway. Since adenosine 2A receptors are also often near dopamine receptors, caffeine could affect dopamine indirectly, also contributing to increased wakefulness.

So if caffeine and psychostimulants like cocaine work in the same brain areas, the basal ganglia, and both affect dopamine, why is one so much less addictive than the other? We're not sure, but it could be that the location of the adenosine 2A receptors makes all the difference. Adenosine 2A receptors tend to be located near D2 type dopamine receptors, while psychostimulants are thought to have a stronger effect on D1 dopamine receptors when they produce their rewarding effects. It is possible that caffeine avoids this pathway somewhat by having receptors that are slightly in the wrong location. It's the little location differences that make a big difference between a line of cocaine and your morning coffee.

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), 10067-75 PMID: 21734299