5-HT1B receptor activation produces rapid antidepressant-like effects in rodents

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2025-02, Vol.247, p.173917, Article 173917
• Main Authors: Clark, Erin A., Wang, Lien, Hanania, Taleen, Kretschmannova, Karla, Bianchi, Massimiliano, Jagger, Elizabeth, Hu, Tingting, Li, Fugang, Gallero-Salas, Yasir, Koblan, Kenneth S., Dedic, Nina, Bristow, Linda J.
• Format: Article
• Language: English
• Subjects: 5-HT1B receptor agonist; Antidepressant; Lateral habenula circuit; Rapid onset; Synaptic plasticity
• ISSN: 0091-3057; 1873-5177; 1873-5177
• DOI: 10.1016/j.pbb.2024.173917

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-HT1B receptor. In this study we utilized CP-94253 to examine whether 5-HT1B 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-HT1B agonist in vitro and that CP-94253 occupies brain 5-HT1B 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-HT1B agonism as a novel treatment approach for major depressive disorder. •CP-94253 produces antidepressant-like effects after acute administration in rodents.•Effectiveness is seen in models commonly used to distinguish ketamine from SSRIs.•Enhanced synaptic plasticity and lateral habenula circuit modulation may contribute.•5-HT1B agonists have potential as novel rapid acting antidepressant agents for MDD.