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
Sumitomo Pharma America, Inc., 84 Waterford Drive, Marlborough, MA 01752, USA.
Sumitomo Pharma America, Inc., 84 Waterford Drive, Marlborough, MA 01752, USA.
Pharmacol Biochem Behav. 2025 Feb;247:173917. doi: 10.1016/j.pbb.2024.173917. Epub 2024 Nov 27.
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 receptor. In this study we utilized CP-94253 to examine whether 5-HT 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 agonist in vitro and that CP-94253 occupies brain 5-HT 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 agonism as a novel treatment approach for major depressive disorder.
氯胺酮因其起效迅速的抗抑郁反应以及对难治性抑郁症患者的有效性而闻名。虽然大多数研究都集中在谷氨酸能机制上，但最近的研究表明，啮齿动物中的抗抑郁样作用依赖于血清素能（5-HT）系统，并提示5-HT受体可能发挥作用。在本研究中，我们使用CP-94253来检验5-HT受体激动是否会产生快速且持续的抗抑郁样作用，重点关注常用于证明对氯胺酮有不同反应的啮齿动物模型和治疗方法。我们首先证实，CP-94253在体外是一种有效的5-HT激动剂，并且在测试剂量下CP-94253能占据脑5-HT受体。CP-94253减少了小鼠强迫游泳试验（FST）中的不动时间，并在小鼠行为表型分析平台SmartCube®中表现出显著的抗抑郁特征。在急性治疗后24小时进行检查时，CP-94253减少了未处理大鼠以及接受慢性α干扰素治疗大鼠的FST不动时间。在记录前24小时接受急性CP-94253治疗的未处理大鼠中，离体海马长时程增强也得到了增强。在暴露于慢性社会挫败应激的小鼠中，急性治疗后1小时和24小时分别在悬尾试验和蔗糖偏好试验中观察到了抗抑郁样作用。最后，小鼠全脑c-fos成像显示，CP-94253调节离散脑区的神经元活动，包括与抑郁症及氯胺酮治疗反应相关的外侧缰核回路。总体而言，这些结果支持进一步研究5-HT激动作为重度抑郁症的一种新治疗方法。
