Acute Blockade of the Serotonin Transporter With Low Doses of Escitalopram Does Not Alter the Behavioural Responses to Acute Psilocybin

Psilocybin, the active compound in psychedelic mushrooms, is being studied as a treatment for depression. Its metabolite psilocin binds to serotonin receptors and the serotonin transporter (5-HTT). In mice lacking 5-HTT, psilocybin failed to cause hyperactivity or head twitches, suggesting 5-HTT might be involved. To test this, researchers gave mice the selective 5-HTT inhibitor escitalopram before psilocybin. Escitalopram did not block psilocybin's effects on movement or head twitches. This indicates that acute blockade of 5-HTT does not directly mediate these behaviors, and the earlier findings in knockout mice likely stem from developmental changes or altered serotonin levels rather than acute transporter function.

Study at a glance

Abstract

ABSTRACT The psychedelic psilocybin has gained popularity in recent years as a therapy for treatment‐resistant depression and has been reported to reduce symptoms of depression and anxiety. Psilocybin's active metabolite, psilocin, possesses a binding affinity for serotonin receptors as well as for the serotonin transporter (5‐HTT). We recently reported that in contrast to wild‐type mice, psilocybin did not induce hyperlocomotion and head‐twitch responses in mice genetically lacking 5‐HTT, suggesting an involvement of 5‐HTT in mediating these effects. To further assess the specific role of 5‐HTT in psilocybin's acute behavioural effects, we treated C57BL/6 mice with the highly selective 5‐HTT inhibitor escitalopram (2.5–5 mg/kg, i.p.) prior to psilocybin administration (1 mg/kg, i.p.), and measured acute behavioural effects including head‐twitch response and locomotor activity. We found that acute psilocybin administration increased locomotor activity and induced head twitches, and that escitalopram did not alter these effects. Our study using low doses of escitalopram reveals no direct involvement of 5‐HTT in mediating the acute effects of psilocybin in mice, and instead suggests that developmental changes and varying serotonin levels may rather explain the absence of psilocybin's acute behavioural effects previously reported in the 5‐HTT homozygous knockout mice.