Epidemiological studies show that individuals exposed to repeated stress, a major trigger of depression, increase their caffeine intake, which correlates inversely with the incidence of depression. However, the mechanism underlying this protective effect is unknown. We used an animal model of chronic unpredictable stress (CUS) to show that caffeine prevents the maladaptive changes caused by CUS in a manner mimicked by the selective blockade of adenosine A 2A receptors (A 2A R). CUS enhanced A 2A R in synapses, and the selective elimination of neuronal A 2A R abrogated CUS modifications. Moreover, A 2A R blockade also afforded a therapeutic benefit, paving the way to consider A 2A R blockers as a strategy to manage the negative impact of chronic stress on mood and memory.

Abstract