Microdosing ketamine in Drosophila does not block serotonin reuptake, but causes complex behavioral changes mediated by glutamate and serotonin receptors
Kelly E. Dunham, Kani H. Khaled, Leah Weizman, B. Venton
Journal of Neurochemistry February 7, 2024 DOI: 10.1111/jnc.16070 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Drosophila melanogaster larvae |
| Interventions | Ketamine escitalopram fluoxetine NMDA receptor antagonists |
| Dose | 1–100 mM |
| Duration | 24 h |
| Topics | Esketamine Ketamine Microdosing Serotonin |
| Key findings | Microdosing ketamine increases locomotion and feeding in fruit fly larvae through NMDA receptor antagonism and serotonin receptor activation, not by inhibiting the serotonin transporter like SSRIs. |
Abstract
Microdosing ketamine is a novel antidepressant for treatment‐resistant depression. Traditional antidepressants, like selective serotonin reuptake inhibitors (SSRIs), inhibit serotonin reuptake, but it is not clear if ketamine shows a similar mechanism. 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 depressive 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 h 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 because of its anesthetic properties. Since microdosing ketamine causes behavioral effects, we further investigated behavioral changes with a SERT16 mutant and low doses of other NMDA receptor antagonists and 5‐HT1A and 2 agonists. Feeding and locomotion changes were similar to ketamine in the mutant, and we found 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, but effects behavior with other mechanisms that should be investigated further.
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 9
- 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
- Role of Ketamine in the Treatment of Psychiatric Disorders Health Psychology Research June 22, 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
and 4 more in the library