A ketamine derivative exerts enhanced antidepressant effects via adenosine signaling.
Na Wang, Chenyu Yue, Xiaofeng Fan, Yuan Gao, Huiping Shang, Yali He, Minmin Luo
Science China. Life sciences October 22, 2026 DOI: 10.1007/s11427-026-3325-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Chronically stressed mice |
| Interventions | 3C-DCK Ketamine |
| Dose | 2 mg/kg |
| Duration | Effects assessed up to 72 h after a single dose |
| Topics | Ketamine Esketamine |
| Keywords | 3c-dck A1 receptor A2a receptor Adenosine Long-lasting antidepressant effects Mpfc Side effects |
| Key points | A single 2 mg/kg dose of 3C-DCK produced rapid antidepressant-like effects in chronically stressed mice lasting up to 72 hours, longer than ketamine, and without hyperlocomotion or ataxia. The authors attribute this to more potent, sustained mPFC adenosine release via lowered ATP/ADP ratio and ENT-dependent efflux, requiring A1 and A2A receptor signalling. They argue adenosine signalling could separate therapeutic efficacy from ketamine's adverse effects. |
Abstract
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 release than ketamine at lower doses. Mechanistically, 3C-DCK lowers the intracellular ATP/ADP ratio, thereby driving equilibrative nucleoside transporter (ENT)-dependent adenosine efflux without inducing neuronal hyperexcitation or extracellular ATP hydrolysis. In chronically stressed mice, a single 2 mg/kg dose produced rapid and durable antidepressant-like effects lasting up to 72 h, exceeding the duration of ketamine. These effects required A1 and A2A receptor signalling and occurred without hyperlocomotion or ataxia. Together, our findings establish adenosine signaling as a druggable axis for dissociating therapeutic efficacy from ketamine-associated adverse effects and provide a framework for the development of next-generation rapid-acting antidepressants.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |