The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT<sub>2A</sub> receptor activation and serotonergic transmission.
Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2025-01-01; 136: 111217
DOI: 10.1016/j.pnpbp.2024.111217
Lire sur PubMed
1. Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 9;136:111217. doi:
10.1016/j.pnpbp.2024.111217. Online ahead of print.
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.
Arias HR(1), Rudin D(2), Luethi D(2), Valenta J(2), Leśniak A(3), Czartoryska
Z(3), Olejarz-Maciej A(4), Doroz-Płonka A(4), Manetti D(5), De Deurwaerdère
P(6), Romanelli MN(5), Handzlik J(4), Liechti ME(2), Chagraoui A(7).
Author information:
(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: .
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-HT2A/2C receptors with similar potency
in the nM range. However, they act as competitive antagonists of the 5-HT2B
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-HT2A receptor activation and serotonergic transmission.
Copyright © 2024. Published by Elsevier Inc.
DOI: 10.1016/j.pnpbp.2024.111217
PMID: 39662723
Conflict of interest statement: Declaration of competing interest We confirm
that there are no known conflicts of interest associated with this publication.
Furthermore, there has been no significant financial support for this work that
could have influenced its outcome.