Adenosine signalling drives antidepressant actions of ketamine and ECT

Adenosine signalling is identified as the central pathway behind the rapid antidepressant actions of ketamine and electroconvulsive therapy (ECT). In mouse models, both treatments trigger strong, fast adenosine surges in mood-regulatory brain regions including the medial prefrontal cortex and hippocampus. Genetic or pharmacological disruption of adenosine receptors A1 and A2A abolishes therapeutic effects, showing that adenosine receptor signalling is required. The medial prefrontal cortex specifically is highlighted as a key driver of antidepressant outcomes. Ketamine is linked to increased intracellular adenosine by modulating cellular metabolism, without causing neuronal hyperactivity. The study also reports ketamine derivatives that potentiate adenosine signalling to improve antidepressant efficacy while reducing side effects, and finds acute intermittent hypoxia can produce antidepressant effects via an adenosine-dependent mechanism.