Microdosing ketamine in Drosophila does not block serotonin reuptake, but causes complex behavioral changes mediated by glutamate and serotonin receptors
Journal of Neurochemistry February 7, 2024 Kelly E. Dunham, Kani H. Khaled, Leah Weizman et al.
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.