Acute Blockade of the Serotonin Transporter With Low Doses of Escitalopram Does Not Alter the Behavioural Responses to Acute Psilocybin
Nina Kleditzsch, James J Gattuso, Anthony J. Hannan, Thibault Renoir
European Journal of Neuroscience December 1, 2025 DOI: 10.1111/ejn.70351 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experiment Peer reviewed |
|---|---|
| Population | C57BL/6 mice |
| Interventions | Escitalopram Psilocybin |
| Dose | escitalopram 2.5–5 mg/kg i.p., psilocybin 1 mg/kg i.p. |
| Topics | Psilocybin Serotonin |
| Keywords | Escitalopram Hallucinogen Serotonin transporter Blockade Serotonin uptake inhibitors 5-HT Receptor Knockout mouse Serotonin reuptake inhibitor Serotonin antagonists Psychopharmacology |
| Key findings | Acute pretreatment with the selective 5-HTT inhibitor escitalopram did not alter psilocybin-induced hyperlocomotion or head-twitch responses in mice, suggesting that 5-HTT is not directly involved in mediating these acute behavioral effects. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 20
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Proceedings of the National Academy of Sciences April 13, 2021
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- The Therapeutic Potential of Psilocybin Molecules May 15, 2021
- Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice Journal of Psychopharmacology December 8, 2010
and 15 more in the library