During periods of chronic stress, we often up our caffeine consumption. This works better than you might expect—the increase can reduce some of the negative effects of long-term stress, including depression and memory deterioration. In a new study published in PNAS, researchers dug further into this finding, examining the signaling networks that caffeine influences within the brain. One of the proteins they identify is a potential treatment target for the symptoms of long-term stress.

Chronic unpredictable stress alters neural circuits in the hippocampus. It dampens mood, reduces memory performance, and increases an individual’s susceptibility to depression. The researchers studied this phenomenon in mice by exposing them to chronic, unpredictable, long-term stress in a variety of forms: cage-tilting, damp sawdust, predator sounds, placement in an empty cage, switching cages, and inversion of day/night light cycles. Just like humans experiencing chronic stress, the mice showed weight loss and memory deterioration. The mice also demonstrated helplessness and loss of interest in stimuli, which are markers of depression in mice.

After being chronically stressed, the mice were exposed to caffeine in their drinking water. As expected, caffeine reduced the mice’s depressive symptoms. Additionally, it improved the memory impairment in these mice, measured via recall of maze-based problem solving and object displacement.

Caffeine acts on proteins called adenosine receptors in the brain, so the researchers examined changes in adenosine A 1 and adenosine A 2A receptor behavior after exposure to chronic stress. In neuroscience, a chemical antagonist is a molecule that interferes with the chemical binding of another molecule to its receptor. In exploring chronic stress-induced changes to neurotransmitter function based on antagonists, they found that A 1 antagonist binding was reduced by chronic stress, whereas A 2A antagonist binding was enhanced. This indicated that the A zA receptors were up-regulated in response to chronic stress, which made it a strong potential target for a drug that could mimic the effects of caffeine.

In exploring the possibility of a drug therapy for the effects of chronic stress, they found that a chemical that selectively blocked the adenosine A 2A receptor mimicked the protective effects of caffeine for chronically stressed mice. This therapy was effective immediately after the exposure to chronic stress had ended, and it was even effective several weeks after chronic stress exposure had concluded, indicating that it may have therapeutic value even if it can’t be administered during or directly after a stressful time period.

Similarly, genetic manipulation of mice to remove their A 2A receptors was also protective against the negative effects of chronic stress. However, this finding is mainly used to support the data showing that A 2A receptors were an effective target for chronic stress drug therapies—gene therapy to knock out a specific neuroreceptor in humans isn’t currently feasible, and it could come with severe side effects.

As a result of these two findings, the researchers conclude that A 2A receptors play an important role in chronic-stress-related physiological changes. They suggest that adenosine receptors may have a general role in controlling mood disorders, which may make them appealing targets for therapies going forward.

PNAS, 2015. DOI: 10.1073/pnas.1423088112 (About DOIs).