THE PROTOTYPICAL PSYCHEDELIC AGENT LSD PRODUCES RAPID ANTIDEPRESSANT EFFECTS VIA 5-HT2B RECEPTOR ACTIVATION
Authors: Bouloufa Amel , Delcourte Sarah , Rovera Renaud , Dkhissi-Benyahya Ouria , Haddjeri *Nasser 
Published: February 2025

Abstract

Background
Recent clinical trials reveal that serotonergic psychedelics, including the prototypical hallucinogen lysergic acid diethylamide (LSD), present a promising potential for treating psychiatric disorders, including treatment-resistant depression. LSD is a potent 5-HT receptors ligand endowed with high affinity for most of all 5-HT subtypes and is regularly used as a valuable pharmacological tool to characterize 5-HT1A and 5-HT2A receptor mediations [1]. Notably, a crystal structure of LSD in complex with the human 5-HT2B receptor has been recently described [2].

Aims & Objectives
Using both in vivo electrophysiological and behavioral paradigms in rodents, the present work was aimed to evaluate the involvement of the 5-HT2B receptor mediation in the action of LSD, firstly on the spontaneous firing activity of rat dorsal raphe (DRN) 5-HT neurons and secondly in modulating rat head twitch response (hallucinatory-like response), ultrasonic vocalization (anxious-like response) and active coping behaviour (despair-like response).

Methods
- Extracellular unitary recordings of DRN 5-HT neurons were performed in anaesthetized rat. LSD (i.v.) was injected until cell firing was completely suppressed both after injection of vehicle or the selective 5-HT2B antagonist RS 127445 (i.v.).
- Rats were exposed to T1 &T2 sessions of 1 to 4 randomly distributed electric shocks until 22-kHz USV emissions. After 24 h, they received a single shock after vehicle administration (T3 session). After 24 h for the T4 session, they received a single shock after acute vehicle or LSD (i.p.) injection in combination with RS 127445 (i.p.) administration.
- Rats were placed in an observation cage and the cumulative number of head twitches (counted during a 30-min period). LSD (i.p.) was injected immediately before the observation while RS 127445 (i,p,) was administered prior to LSD administration.
- For the forced swimming test (FST), rats experienced a pre-test session (15 min) followed 24 h later by a test session (5 min). Vehicle or RS 127445 (i.p.) were injected acutely before vehicle or LSD (i.p.) that were administered 5 days before the test session.

Results
- Acute administration of LSD suppressed totally DRN 5-HT neurons firing rate. Importantly, the selective 5-HT2B receptor antagonist RS 127445 [3] prevented significantly the suppressant effect of LSD.
- Acute administration of LSD induced i) an increase of the head twitch response, ii) a suppression of the duration of foot shock– induced USV and iii) a significant decrease of immobility time in the FST. Notably, the latter actions of LSD were significantly counteracted by a prior administration of RS 127445.

Conclusion
Collectively, the present results suggest for the first time that 5-HT2B receptors play a permissive role in the antidepressant effects of serotonergic psychedelics.

References
[1]Passie T, et al. (2008) CNS Neurosci Ther. 14(4):295-314.
[2]Wacker D, et al. (2017) Cell. 168(3):377-389.
[3]Bonhaus, D. et al. (1999) Brit J Pharmacol, 127, 1075–1082.