HCN channel inhibitor induces ketamine-like rapid and sustained antidepressant effects in chronic social defeat stress model
Min Cai, Yingbo Zhu, M. R. Shanley, Carole Morel, Stacy M. Ku, Hongxing Zhang, Yuan Shen, Allyson K. Friedman, Ming-Hu Han
Neurobiology of Stress August 1, 2023 DOI: 10.1016/j.ynstr.2023.100565 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | CSDS-susceptible mice |
| Dose | single-dose |
| Duration | 13 days |
| Measures | forced swim test, sucrose preference test, social interaction test |
| Topics | Esketamine Ketamine |
| Key points | Acute administration of the HCN channel inhibitor DK-AH 269 produces rapid and sustained antidepressant-like effects in mice, lasting up to 13 days. |
Abstract
Repeated, long-term (weeks to months) exposure to standard antidepressant medications is required to achieve treatment efficacy. In contrast, acute ketamine quickly improves mood for an extended time. Recent work implicates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in mediating ketamine's antidepressant effects. In this study, we directly targeted HCN channels and achieved ketamine-like rapid and sustained antidepressant efficacy. Our in vitro electrophysiological recordings first showed that HCN inhibitor DK-AH 269 (also called cilobradine) decreased the pathological HCN-mediated current (Ih) and abnormal hyperactivity of ventral tegmental area (VTA) dopamine (DA) neurons in a depressive-like model produced by chronic social defeat stress (CSDS). Our in vivo studies further showed that acute intra-VTA or acute systemic administration of DK-AH 269 normalized social behavior and rescued sucrose preference in CSDS-susceptible mice. The single-dose of DK-AH 269, both by intra-VTA microinfusion and intraperitoneal (ip) approaches, could produce an extended 13-day duration of antidepressant-like efficacy. Animals treated with acute DK-AH 269 spent less time immobile than vehicle-treated mice during forced swim test. A social behavioral reversal lasted up to 13 days following the acute DK-AH 269 ip injection, and this rapid and sustained antidepressant-like response is paralleled with a single-dose treatment of ketamine. This study provides a novel ion channel target for acutely acting, long-lasting antidepressant-like effects.
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 |
Citations in the library
Cited by 6
- New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity Cell Death Discovery May 1, 2024
- A comparative assessment of the antidepressant efficacy of ketamine, psilocybin, and fluoxetine in a chronic stress model Scientific Reports November 26, 2025
- Time‐Dependent Therapeutic Effect of S ‐Ketamine on PTSD Mediated by VTA‐OFC Dopaminergic Neurocircuit Advanced Science September 25, 2025
- Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery. Biomedicines June 1, 2026
- Towards Novel Antidepressant Strategies: A Comparative Study of Ketamine, Psilocybin, and Fluoxetine in a Chronic Stress Model Research Square October 7, 2025
and 1 more in the library
Cites 13
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern‐era clinical studies Acta Psychiatrica Scandinavica October 30, 2020
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine Current Neuropharmacology March 10, 2016
and 8 more in the library