Validation of the forced swim test in Drosophila, and its use to demonstrate psilocybin has long-lasting antidepressant-like effects in flies

Psilocybin has been shown to be a powerful, long-lasting antidepressant in human clinical trials and in rodent models. Although rodents have commonly been used to model psychiatric disorders, Drosophila have neurotransmitter systems similar to mammals and many comparable brain structures involved in similar behaviors. The forced swim test (FST), which has been used extensively to evaluate compounds for antidepressant efficacy, has recently been adapted for Drosophila. The fly FST has potential to be a cost-effective, high-throughput assay for evaluating potential antidepressants. For this study we pharmacologically validated the fly FST using methamphetamine, DL-alpha-methyltyrosine, and the antidepressant citalopram. While methamphetamine and DL-alpha-methyltyrosine altered overall locomotor activity in the Drosophila Activity Monitor System (DAMS), they had no significant impact on measures of immobility in the FST. Conversely, chronic citalopram decreased measures of immobility in the FST in both sexes without increasing DAMS activity. We used the validated FST to evaluate the antidepressant-like effects of high (3.5 mM) and low (0.03 mM) doses of psilocybin. Both doses of psilocybin significantly reduced measures of immobility in male flies, but not females. 0.03 mM had an effect size comparable to chronic citalopram, and 3.5 mM had an effect size approximately twice that of chronic citalopram.

Automated summary

Psilocybin has demonstrated strong and long-lasting antidepressant effects in human clinical trials and rodent models. This study validates the use of the fly forced swim test (FST) as a cost-effective and high-throughput method for evaluating potential antidepressants. Methamphetamine and DL-alpha-methyltyrosine had no impact on immobility measures in the FST, while chronic citalopram decreased immobility in both male and female flies. High and low doses of psilocybin significantly reduced immobility measures in male flies, with the low dose having a similar effect to chronic citalopram and the high dose having approximately twice the effect size.