Mice lacking the serotonin transporter do not respond to the behavioural effects of psilocybin.

Psilocybin, a serotonergic psychedelic, shows therapeutic potential for depression and anxiety disorders. In a study using serotonin transporter knockout mice—a model for anxiety and depression—a single dose of psilocybin (1 mg/kg) failed to produce head-twitch or hyperlocomotor responses in knockout animals, unlike wild-type mice. Psilocybin did not alter anxiety- or depressive-like behaviors in either genotype, though a trend toward reduced immobility in the Porsolt swim test appeared in female wild-type mice. Female knockout mice uniquely showed anhedonia-like behavior. The findings indicate that functional serotonin transporters are necessary for psilocybin's acute behavioral effects, with implications for pharmacogenetics in humans.

Study at a glance

Abstract

Psilocybin is a serotonergic psychedelic with therapeutic potential for several neuropsychiatric disorders, including depression and anxiety disorders. Serotonin transporter (5-HTT) knockout mice (KO) are a well-validated mouse model of anxiety/depression and are relevant to both chronic treatment with serotonin transporter reuptake inhibitors (SSRIs) and polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR) associated with depression/anxiety and resistance to classic antidepressant treatments. However, there is yet to be a study assessing the effect of psilocybin in 5-HTT KO mice. We investigated the effects of a single dose of psilocybin (1 mg/kg) on locomotor activity and the head-twitch response as well as anxiety- and depressive-like behaviour in KO versus wild-type (WT) mice using the light-dark box and Porsolt swim test respectively. We found that both the psilocybin-induced head-twitch and hyperlocomotor responses observed in WT mice were completely absent in KO animals. In female WT mice only, psilocybin was also able to block the weight loss observed one day after intraperitoneal injection. While psilocybin did not alter anxiety- and depression-like behaviours for both genotypes, we revealed a genotype-specific trend for a main effect of treatment for WT females (p = 0.054) in the Porsolt swim test. Finally, we found that only female KO mice exhibit anhedonia-like behaviour in the saccharin-preference test. Our findings highlight the complexity of psilocybin's effects and suggest that functional integrity of 5-HTT is essential for psilocybin's acute behavioural effects. This could also have implications for pharmacogenetics, including individuals with polymorphisms or mutations in 5-HTT.