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) via Semantic Scholar
Summary
AI-generated from the abstractA single dose of the HCN channel inhibitor DK-AH 269 (cilobradine) produces rapid and sustained antidepressant-like effects in mice subjected to chronic social defeat stress, lasting up to 13 days. The compound reduces pathological HCN-mediated currents and abnormal hyperactivity of dopamine neurons in the ventral tegmental area. Treated mice showed normalized social behavior, restored sucrose preference, and less immobility in the forced swim test compared to vehicle-treated animals. These effects parallel those of a single dose of ketamine, suggesting HCN channels as a novel target for fast-acting, long-lasting antidepressants.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | CSDS-susceptible mice |
| Dose | single-dose |
| Duration | 13 days |
| Keywords | Medicine |
| Key finding | 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.