The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT2A receptor activation and serotonergic transmission

Hugo R Arias; Deborah Rudin; Dino Luethi; Jan Valenta; Anna Leśniak; Zofia Czartoryska; Agnieszka Olejarz-Maciej; Agata Doroz-Płonka; Dina Manetti; Philippe De Deurwaerdère; Maria Novella Romanelli; Jadwiga Handzlik; Matthias E Liechti; Abdeslam Chagraoui

doi:10.1016/j.pnpbp.2024.111217

The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT_2A receptor activation and serotonergic transmission

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 9:136:111217. doi: 10.1016/j.pnpbp.2024.111217. Online ahead of print.

Affiliations

¹ Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA.
² Division of Clinical Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
³ Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
⁴ Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Krakow, Poland.
⁵ Department of Neurosciences, Psychology, Drug Research and Child Health Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Italy.
⁶ Centre National de la Recherche Scientifique, Institut des Neurosciences Intégratives et Cognitives d'Aquitaine, UMR 5287, Bordeaux, France.
⁷ Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen, France; Différenciation et Communication Neuroendocrine, Endocrine et Germinale Laboratory, Institute for ResearchDr.nd Innovation in Biomedicine of Normandy (IRIB), University of Rouen, INSERM 1239, 76000 Rouen, France. Electronic address: Abdeslam.chagraoui@univ-rouen.fr.

PMID: 39662723
DOI: 10.1016/j.pnpbp.2024.111217

Abstract

The antidepressant-like activity of two psychoplastogens, ibogainalog (IBG) and ibogaminalog (DM506), was studied in naïve mice using the forced swim test (FST) and tail suspension test (TST). The behavioral results showed that a single administration of 25 mg/kg DM506 or 10 mg/kg IBG induced antidepressant-like activity in naïve mice in a volinanserin-sensitive manner that persisted for 72 h. Similar results were observed using the chronic immobilization stress (CIS) test, in which depression symptoms were reduced for 48 h. To assess the contribution of serotonergic and/or norepinephrinergic neurotransmission, serotonin (5-HT) and norepinephrine (NE) levels were depleted. The reduction in 5-HT levels, but not NE levels, inhibited the antidepressant-like activity of ibogalogs, suggesting that serotonergic transmission may play a more significant role than norepinephrinergic transmission. Concurrently, DM506, IBG, and TBG (derived from tabernanthine) inhibited monoamine transporters with the following order of selectivity: SERT > NE transporter > dopamine transporter. The IBG exhibited the highest selectivity for SERT. Only TBG inhibited monoamine oxidase A activity, indicating its relatively minor role. Radioligand and functional assays showed that all ibogalogs bind to the 5-HT₂ receptor subfamily (DM506 > IBG > TBG) and fully activate 5-HT_2A/2C receptors with similar potency in the nM range. However, they act as competitive antagonists of the 5-HT_2B receptor, with DM506 as an exception, exhibiting partial but potent agonist activity. In conclusion, ibogalogs induce acute and sustained antidepressant-like activity in naïve and depressed mice through mechanisms involving 5-HT_2A receptor activation and serotonergic transmission.

Keywords: 5-HT receptors; Antidepressant activity; Ibogalogs; MAO-B/A; Monoamine transporters; Psychoplastogens.