5-HT1B receptor activation produces rapid antidepressant-like effects in rodents.
Erin A Clark, Lien Wang, Taleen Hanania, Karla Kretschmannova, Massimiliano Bianchi, Elizabeth Jagger, Tingting Hu, Fugang Li, Yasir Gallero-Salas, Kenneth S Koblan, Nina Dedic, Linda J Bristow
Pharmacology, Biochemistry, and Behavior February 1, 2025 DOI: 10.1016/j.pbb.2024.173917 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rodents (mice and rats) |
| Intervention | CP-94253 |
| Duration | 1 hour and 24 hours after acute treatment |
| Topics | Neuroplasticity Serotonin |
| Keywords | 5-ht1b receptor agonist Lateral habenula circuit Rapid onset Depression treatment Neuroscience research Serotonin receptors Antidepressant drugs Brain circuits |
| Citations | 5 |
| Key points | 5-HT1B receptor agonism with CP-94253 produces rapid and sustained antidepressant-like effects in rodents, modulates the lateral habenula circuit, and enhances hippocampal long-term potentiation. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 3
- An exploration of the relationships between the effects of psilocybin on behavior, 5-HT 2A receptor occupancy, and neuroplastic effects in mice Journal of Psychopharmacology January 6, 2026
- Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics Journal of Psychopharmacology August 27, 2025
- Convergent increases in serotonin 1B receptor binding following ketamine and electroconvulsive therapy: a multi-centre bayesian re-analysis of PET data Molecular Psychiatry July 8, 2026
Cites 23
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
and 18 more in the library