Microdosing ketamine in Drosophila does not inhibit SERT like SSRIs, but causes behavioral changes mediated by glutamate and serotonin receptors

Ketamine, recently FDA-approved for treatment-resistant depression, does not work like traditional SSRIs at low doses. In fruit fly larvae, which have a serotonin system similar to mammals, 1 mM ketamine did not affect serotonin reuptake but increased locomotion and feeding. Low doses of SSRIs (escitalopram and fluoxetine) inhibited serotonin reuptake and also increased feeding and locomotion. At a high dose (100 mM), ketamine inhibited serotonin reuptake and increased serotonin concentrations but decreased locomotion and feeding due to anesthetic effects. Low doses of other NMDA receptor antagonists increased feeding, while serotonin receptor agonists increased locomotion, suggesting ketamine affects behavior through multiple mechanisms, not by blocking serotonin reuptake like SSRIs.

Study at a glance

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.