Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice
M. Bowman, Melissa Vitela, K. Clarke, Wouter Koek, Lynette C. Daws
International Journal of Molecular Sciences October 1, 2020 DOI: 10.3390/ijms21207581 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Wild-type mice and mice constitutively lacking SERT or PMAT |
| Intervention | Ketamine |
| Topics | Esketamine Ketamine Serotonin |
| Key findings | Ketamine inhibited serotonin clearance in wild-type mice, but not in mice lacking SERT or PMAT, and the antidepressant-like effects of ketamine were lost in those knockout mice. |
Abstract
Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.
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 7
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation Neurobiology of Stress April 20, 2022
- Ketamine and epigenetic processes in depression, intersection between serotonergic and glutamatergic pathways Journal of Psychedelic Studies March 29, 2024
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
- Microdosing ketamine in Drosophila does not inhibit SERT like SSRIs, but causes behavioral changes mediated by glutamate and serotonin receptors bioRxiv Preprint Server November 7, 2023
and 2 more in the library
Cites 17
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents Proceedings of the National Academy of Sciences January 15, 2020
- (R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism The International Journal of Neuropsychopharmacology July 16, 2019
and 12 more in the library