Adenosine on the common path of rapid antidepressant action: The coffee paradox

Summary

Introduction As Claude Bernard understood in laying the foundations of experimental medicine, each scientific generation brings us closer to mechanistic truth, yet complete understanding remains elusive (1). This has been particularly evident in psychiatric therapeutics, where chance preceded knowledge for a long time. For over twenty years now, we had evidence suggesting that ketamine was a rapid anti-depressant. We knew the electrically charged scalpel of electroconvulsive therapy worked when nothing else did. And we had long suspected that depriving people of sleep benefited them in a transient way. All we were lacking was the mechanistic thread connecting these varied interventions, the common path which might allow for rational, instead of empirical, therapeutic development. In a study that demonstrates what modern neuroscience can do when technical virtuosity meets conceptual clarity, Yue and colleagues led by Professor Min-Min Luo now provide that thread (2). Using genetically encoded adenosine sensors, a comprehensive genetic and pharmacological dissection, and immediate therapeutic translation they show that adenosine signalling is the convergent mechanism of rapid-acting antidepressant therapies. It is a new way of thinking about treatment-resistant depression and not just an incremental science. The technical achievement The precise timing is what gives the work its compelling quality. The authors applied GRABAdo1.0, a GPCR-based sensor for adenosine, to monitor online adenosine changes in mood-regulating circuits (2). Injection of ketamine (10 mg/kg) and application of electroconvulsive therapy resulted in a substantial spike in extracellular adenosine in the medial prefrontal cortex and hippocampus with peak amplitudes of ∼15% ΔF/F, which peaked in ∼500 s and lasted about 30 minutes above the baseline (Extended Data Fig. 1d–h in ref. 2). The specificity to regions is also telling. Even though adenosine increases occurred in the mPFC and hippocampus, no ...