Microdosing ketamine in Drosophila does not block serotonin reuptake, but causes complex behavioral changes mediated by glutamate and serotonin receptors

Ketamine, when given at very low (micro) doses, increases movement and feeding in fruit fly larvae, but through a different mechanism than standard antidepressants such as SSRIs. At 1 mM, ketamine did not alter serotonin levels yet still boosted locomotion and feeding, whereas low doses of the SSRIs escitalopram and fluoxetine inhibited the serotonin transporter (dSERT) and similarly increased these behaviors. At a high dose (100 mM), ketamine blocked dSERT and raised serotonin, but reduced movement and feeding due to anesthetic effects. Experiments with mutant flies and other drugs suggest ketamine's behavioral effects come from NMDA receptor antagonism (which increases feeding) and serotonin receptor activation (which increases locomotion), not from acting on the serotonin transporter like SSRIs.

Study at a glance

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.