Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine.
Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei, Si-Rui Sun, Yu-Qiang Ding, Li-Ming Zhang, Yun-Feng Li
British Journal of Pharmacology December 1, 2024 DOI: 10.1111/bph.17324 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine PCPA 5 7-DHT NBQX |
| Dose | 10 mg·kg-1, i.p. |
| Duration | 60 min and 24 h post-injection |
| Topics | Ketamine Serotonin Esketamine |
| Keywords | 5‐ht Ampa Antidepressant Sustained Ketamine-assisted therapy Mood disorder therapy Neurotransmitters serotonin Brain chemistry Neurore |
| Citations | 13 |
| Key points | Sustained but not rapid antidepressant-like effects of ketamine require serotonergic neurotransmission and involve AMPA receptors. |
Abstract
The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain. 60 min after injection, ketamine (10 mg·kg-1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg-1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice. This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.
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 4
- Ketamine treatment alleviates suicide ideation in high-risk populations: a systematic review and meta-analysis Epidemiology and Psychiatric Sciences 2026
- Investigation of Potential Therapeutic Effects of New Rapid-Acting Antidepressant Drugs (RAADs) Using Stress-Based Models of Depression Biomolecules August 24, 2026
- Efficacy and safety evaluation of intravenous esketamine in alleviating perioperative depressive symptoms in Parkinson’s disease: a randomized controlled trial BMC Anesthesiology April 15, 2026
- Ascorbic acid enhances antidepressant-like efficacy of esketamine: Hippocampal TARP-γ8-containing AMPA receptors mediate synaptic modulation. Neurotherapeutics November 11, 2025
Cites 12
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder The Journal of Clinical Psychiatry July 13, 2010
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacology & Therapeutics July 1, 2019
and 7 more in the library