Ketamine exerts rapid antidepressant effects but is limited by dissociative and abuse-related side effects, highlighting the need for safer alternatives. Here, we identify 3C-DCK, a rationally designed ketamine derivative, through adenosine dynamics in the medial prefrontal cortex (mPFC). Using the GRABAdo1.0 sensor, we show that 3C-DCK elicits more potent and sustained extracellular adenosine...
Ketamine and electroconvulsive therapy (ECT) achieve rapid remission in treatment-resistant depression. However, their mechanisms of action—the understanding of which is essential for refining therapeutic precision—remain unclear1, 2–3. Here, using mouse models, we identify adenosine signalling as a central pathway that underlies the antidepressant effects of these interventions. Results from...