5-HT 1B receptor activation produces rapid antidepressant-like effects in rodents.

Ketamine is noted for its rapid onset antidepressant response and effectiveness in patients with treatment resistant depression. While most research has focused on glutamatergic mechanisms, recent studies show that antidepressant-like effects in rodents are dependent upon the serotonergic (5-HT) system and suggest a potential contribution of the 5-HT _1B receptor. In this study we utilized CP-94253 to examine whether 5-HT _1B receptor agonism produces rapid and sustained antidepressant-like effects, focusing on rodent models and treatment approaches commonly used to demonstrate the differentiated response to ketamine. We first confirmed that CP-94253 is a potent 5-HT _1B agonist in vitro and that CP-94253 occupies brain 5-HT _1B receptors at the doses tested. CP-94253 reduced immobility in the mouse forced swim test (FST) and exhibited a prominent antidepressant signature in the mouse-behavior phenotyping platform SmartCube®. When examined 24 h after acute treatment, CP-94253 reduced FST immobility in both naïve rats and in rats receiving chronic interferon alpha treatment. Ex vivo hippocampal long-term potentiation was also enhanced in naïve rats receiving acute CP-94253 treatment, 24 h prior to the recordings. In mice exposed to chronic social defeat stress, antidepressant-like effects in the tail suspension and sucrose preference tests were seen 1 h and 24 h after acute treatment, respectively. Finally, whole brain c-fos imaging in mice showed that CP-94253 modulates neuronal activity in discrete brain regions including the lateral habenula circuit implicated in depression and the ketamine treatment response. Collectively these results support the further investigation of 5-HT _1B agonism as a novel treatment approach for major depressive disorder.
Competing Interests: Declaration of competing interest At the time these studies were conducted the authors were employees of the following companies: Sumitomo Pharma America Inc. (Erin Clark, Lien Wang, Kenneth Koblan, Nina Dedic, Linda Bristow); Psychogenics Inc. (Taleen Hanania, Karla Kretschmannova); Ulysses Neuroscience Ltd. (Massimiliano Bianchi); Sygnature Discovery (Elizabeth Jagger); Gubra ApS (Yasir Gallero-Salas); HD Biosciences Company Ltd. (Tingting Hu, Fugang Li).
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