Repeated adenosine A1 receptor antagonism rewires ventral hippocampus-ventral tegmental area transmission and enhances stress-coping responses

Despite decades of research, antidepressant therapies are ineffective in many patients, and the rewiring of neuronal networks during depression has remained largely unexplored. Emerging evidence indicates that unbalanced inhibition/ excitation and dysregulations of ventral tegmental area (VTA) dopamine (DA) neuron activity are correlated with depression. Recently, caffeine and adenosine receptor antagonists were found to modulate VTA DA neuron activity, and investigations in both, humans and rodents, indicate that these receptors might serve as targets to treat depression. We employed a system-oriented approach and electrophysiology measurements to explore the impact of the adenosine A1 receptor antagonist DPCPX on the ventral hippocampus (vHPC)-VTA circuit and its ability to affect behavioral responses in forced swim and elevated plus maze tests. A single exposure to DPCPX reduced VTA DA neuron activity at doses known to elicit anxiety. With repeated exposure, a lower dose of DPCPX sufficed to stabilize DA neuron firing via vHPC and to prevent an influence of tetrahydrodeoxycorticosterone or forced swim task (FST), but not of elevated plus maze (EPM), on VTA DA neuron activity. Vice versa, repeated DPCPX enhanced active stress coping behavior in FST, but failed to exert an action in EPM. Our data indicate that repeated A1R antagonism in vHPC can rewire the vHPC - NAc - VTA circuitry to enhance stress resilience by orchestrating VTA DA neuron activity. As reinforced stress resilience may boost antidepressant therapy, A1 receptor antagonism may prove to be a promising strategy in the fight against major depressive disorder.