Adenosine A2A receptors in the nucleus accumbens regulate stress resilience and predict susceptibility to stress-induced affective disturbances

Individual variability in stress responses contributes to susceptibility or resilience to mood and anxiety disorders. The adenosinergic system, particularly A1 and A2A receptors, modulates synaptic activity in brain regions involved in emotional regulation, including the nucleus accumbens (NAc), a central hub of reward processing and stress responsivity. Despite high adenosine receptor expression in the NAc, their specific role in stress resilience remains poorly understood. Here, we investigated the effects of 10 days of chronic social defeat stress (CSDS) on A1 and A2A receptor expression and synaptic proteins in the NAc of male C57BL/6 mice categorized as resilient (RES) or susceptible (SS) based on their sociability. SS mice exhibited social avoidance and elevated anxiety-like behaviors, whereas RES mice behaved comparably to controls. Neurochemical analyses revealed that RES mice had lower A2A receptor mRNA levels and decreased PSD-95 expression, suggesting reduced excitatory synaptic tone, while A1 receptor and gephyrin levels remained unchanged. To assess whether baseline adenosine signaling predicts stress vulnerability, we applied a caffeine responsiveness index. Caffeine, a non-selective adenosine receptor antagonist (7.5 mg/kg, i.p.), was used to classify Swiss mice as caffeine-responsive or non-responsive based on its psychostimulant effects, which are primarily attributed to A2A receptor antagonism. Following a 14-day washout, animals were exposed to chronic variable stress (CVS), and caffeine-responsive mice showed deficits in motivational and exploratory behaviors. Together, these findings indicate that lower A2A receptor signaling in the NAc supports stress resilience, whereas heightened baseline caffeine sensitivity may predict vulnerability to stress-induced affective disturbances.