HCN channel inhibitor induces ketamine-like rapid and sustained antidepressant effects in chronic social defeat stress model.

Autor: Cai M; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Zhu Y; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; China Shenzhen Naowunao Network Technology Co.,Ltd., Shenzhen, Guangdong, China., Shanley MR; Department of Biological Sciences, Hunter College, Biology and Biochemistry PhD Program, Graduate Center, The City University of New York, New York, NY, USA., Morel C; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ku SM; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Zhang H; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Shen Y; Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Friedman AK; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Han MH; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, Guangdong, China.
Jazyk: angličtina
Zdroj: Neurobiology of stress [Neurobiol Stress] 2023 Aug 19; Vol. 26, pp. 100565. Date of Electronic Publication: 2023 Aug 19 (Print Publication: 2023).
DOI: 10.1016/j.ynstr.2023.100565
Abstrakt: 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 ( I h ) 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.
Competing Interests: The authors have no conflicts of interests concerning this work.
(© 2023 The Authors. Published by Elsevier Inc.)
Databáze: MEDLINE
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