Microdosing ketamine in Drosophila does not inhibit SERT like SSRIs, but causes behavioral changes mediated by glutamate and serotonin receptors
Kelly E. Dunham, Kani H. Khaled, Leah Weizman, B. Jill Venton
bioRxiv Preprint Server November 7, 2023 preprint DOI: 10.1101/2023.11.07.566121 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Drosophila melanogaster larvae |
| Interventions | Ketamine escitalopram fluoxetine NMDA receptor antagonists 5-HT1A and 2 agonists |
| Dose | 1-100 mM |
| Duration | 24-hour feeding |
| Topics | Esketamine Ketamine Microdosing Serotonin |
| Key findings | At microdoses, ketamine does not inhibit serotonin reuptake like SSRIs but affects behavior through other mechanisms, including NMDA receptor antagonism and serotonin receptor agonism. |
Abstract
Recently, the FDA approved microdosing ketamine for treatment resistant depression. Traditional antidepressants, like serotonin selective reuptake inhibitors (SSRIs), block serotonin reuptake, but it is not clear if ketamine blocks serotonin reuptake. Here, we tested the effects of feeding ketamine and SSRIs to Drosophila melanogaster larvae, which has a similar serotonin system to mammals, and is a good model to track depression behaviors, such as locomotion and feeding. Fast-scan cyclic voltammetry (FSCV) was used to measure optogenetically-stimulated serotonin changes, and locomotion tracking software and blue dye feeding to monitor behavior. We fed larvae various doses (1-100 mM) of antidepressants for 24 hours and found that 1 mM ketamine did not affect serotonin, but increased locomotion and feeding. Low doses (≤ 10 mM) of escitalopram and fluoxetine inhibited dSERT and also increased feeding and locomotion behaviors. At 100 mM, ketamine inhibited dSERT and increased serotonin concentrations, but decreased locomotion and feeding due to its anesthetic properties. Since microdosing ketamine causes behavioral effects, we also investigated behavior changes with low doses of other NMDA receptor antagonists and 5-HT1A and 2 agonists, which are other possible sites for ketamine action. NMDA receptor antagonism increased feeding, while serotonin receptor agonism increased locomotion, which could explain these effects with ketamine. Ultimately, this work shows that Drosophila is a good model to discern antidepressant mechanisms, and that ketamine does not work on dSERT like SSRIs at microdoses, but affects behavior with other mechanisms.
Comparable studies
Other experimental studies on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Microdosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1), and Interaction (Grapefruit Juice) Profiles of Celiprolol Following the Oral Microdose and Therapeutic Dose Healthy volunteers matched for SLCO2B1 genotype | 2011 | Pharmacokinetic study | n = 30 |
| Microdosing psychedelics has no impact on cognitive function in naturalistic settings Participants during their microdosing regimen | 2023 | Observational within-subjects design | n = 17 |
| PK and PK / PD Modeling of Bcl2 Inhibitor S65487 in Patients With AML and Investigation of Nonlinearity With Microdosing Phase I/II cancer patients and healthy volunteers | 2026 | Pharmacokinetic/pharmacodynamic modeling study | |
| Technical pen-based printhead for high-precision microdosing of personalized therapies. | 2026 | Experimental study | |
| Analysis of Serotonin in Caenorhabditis Elegans Subjected to Micro-Dosing with Psilocybin| Iris Publishers Caenorhabditis elegans | 2025 | Experimental study |
Citations in the library
Cites 7
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment‐resistant depression Clinical Case Reports April 4, 2021
- A case series of group-based ketamine-assisted psychotherapy for patients in residential treatment for eating disorders with comorbid depression and anxiety disorders. Journal of Eating Disorders May 6, 2022
- Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions. Brain Sciences March 12, 2022
- Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice International Journal of Molecular Sciences October 1, 2020
and 2 more in the library