Purinergic modulation of major depressive disorder: Experimental findings, pathogenesis and therapeutic opportunities

Major depressive disorder (MDD) is a mental illness characterized primarily by persistent low mood and anhedonia. Traditional monoamine antidepressants have not achieved entirely satisfactory clinical efficacy. Recent studies have revealed that extracellular adenosine 5'-triphosphate (ATP), adenosine, and their P2/P1 receptor (R)-mediated purinergic signaling play a significant role in the pathogenesis of depression. This review first describes what is known regarding the mechanisms of ATP release in glial cells and neurons, particularly the role of reduced ATP release by astrocytes in decreasing synaptic plasticity and dopaminergic signaling, leading to depressive-like behavior. Subsequently, it summarizes the distinct roles of the purinergic ionotropic P2XRs (especially P2X7) and metabotropic P2YRs in regulating neuroinflammation and synaptic plasticity. It then reviews the role of adenosine metabolic imbalance and altered function of adenosine A1 and A2ARs in further promoting pathological processes in depression. Finally, based on the aforementioned mechanisms, intervention strategies targeting different purinergic pathways are briefly outlined, including P2X7R antagonists, adenosine receptor modulators and S-adenosylmethionine (SAMe), including outstanding challenges for their translation towards a clinical application.