Effects of Transient Administration of the NMDA Receptor Antagonist MK-801 in Drosophila melanogaster Activity, Sleep, and Negative Geotaxis

Abstract

MK-801, also called dizocilpine, is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in animal research to model schizophrenia-like phenotypes. Although its effects in rodents are well characterised, little is known about the outcomes of this drug in other organisms. In this study, we characterise the effects of MK-801 on the locomotion, sleep, and negative geotaxis of the fruit fly Drosophila melanogaster. We observed that acute (24 h) and chronic (7 days) administration of MK-801 enhanced negative geotaxis activity in the forced climbing assay for all tested concentrations (0.15 mM, 0.3 mM, and 0.6 mM). Moreover, acute administration, but not chronic, increased the flies’ locomotion in a dose-dependent matter. Finally, average sleep duration was not affected by any concentration or administration protocol. Our results indicate that acute MK-801 could be used to model hyperactivity phenotypes in Drosophila melanogaster. Overall, this study provides further evidence that the NMDA receptor system is functionally conserved in flies, suggesting the usefulness of this model to investigate several phenotypes as a complement and replacement of the rodent models within drug discovery.

Neuronal mechanisms regulating locomotion in adult Drosophila

“…Discoveries in translational research in Drosophila models can provide valuable therapeutic insights into the treatment of locomotor disorders in mammals, including humans. Drugs or interventions found effective in modulating locomotion in Drosophila can be tested in mammalian models and ultimately in clinical trials in humans (Moulin et al., 2023; Ramos‐Hryb et al., 2021; Su, 2019).…”

Evidence for Prepulse Inhibition of Visually Evoked Motor Response in Drosophila melanogaster

“…We observed that the prepulse effect was partially disrupted by exposing the flies to MK-801. We employed three different concentrations based on previous experiments describing the effects of MK-801 on Drosophila behavior [ 33 ]. First, 0.15 mM MK-801 partially disrupted PPI within the 3 s interval testing, although we did not detect significant effects across all other intervals.…”

“…Importantly, Drosophila features conserved homologues of key mammalian genes encoding NMDA receptor subunits, specifically NR1 and NR2, which exhibit common genetic and structural attributes [ 46 ]. For instance, the NR1 glycine-binding and NR2 glutamate-binding domains display conserved amino acid sequences [ 47 , 48 , 49 ], and functional similarities in NMDA receptors concerning signaling and neuronal plasticity are well established [ 33 , 49 , 50 , 51 ]. Moreover, pharmacological parallels between MK-801 interactions with mammalian and invertebrate NMDA receptors have been identified, including blocking NMDA-dependent processes [ 51 , 52 , 53 ] and targeting the conserved asparagine residue in NR1 subunits [ 48 , 49 , 50 , 53 ].…”

“…Prepulse inhibition experiments were performed by treating the flies with MK-801 (0.6, 0.3, or 0.15 mM) for 24 h via homogenization in the fly food, from a 5 mM stock solution, during the preparation of the instant food mix previously described. The chosen concentrations were based on a preceding study from our group [ 33 ], where MK-801 effectively replicated hyperlocomotion phenotypes similar to rodent models in a dose-dependent manner. For the stimuli desensitization protocol, we administered the highest concentration used in this study (0.6 mM), as higher dosages of MK-801 have been shown to have a greater effect on startle habituation in rodents [ 34 ].…”