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A Single Administration of the Atypical Psychedelic Ibogaine or its Metabolite Noribogaine Induces an Antidepressant-like Effect in Rats

preprint
submitted on 18.03.2020 and posted on 19.03.2020 by Paola Rodríguez, Jessika Urbanavicius, José Pedro Prieto, Sara Fabius, Ana Laura Reyes, Vaclav Havel, Dalibor Sames, Cecilia Scorza, Ignacio Carrera
Anecdotal reports and open label case studies in humans indicated that the psychedelic alkaloid ibogaine exert profound anti-addictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite noribogaine, in substance use disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose and time-dependence) induced by the acute ibogaine and noribogaine (20 and 40 mg/kg, i.p.) administration in rats using the forced swim test (FST). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine’s FST effect was short lived (30 minutes) and correlated with high brain concentrations (estimated > 8 mM of free drug), while the ibogaine’s antidepressant-like effect was significant at 3 hours. At this time point, both ibogaine and noribogaine were present in rat brain, at concentrations which cannot produce the same behavioral outcome on their own (ibogaine ~ 0.5 mM, noribogaine ~ 2.4 mM). Our data suggest a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.

Funding

Agencia Nacional de Investigación e Innovación (ANII-Uruguay, Fondo María Viñas FMV_1_2014_1_103488)

Comisión Sectorial de Investigación Científica (Universidad de la República, CSIC-Grupos I+D 1063)

Programa de Desarrollo de las Ciencias Básicas (PEDEClBA - Uruguay)

Columbia University, New York, NY, USA

History

Email Address of Submitting Author

icarrera@fq.edu.uy

Institution

Universidad de la República

Country

Uruguay

ORCID For Submitting Author

0000-0002-6053-3162

Declaration of Conflict of Interest

No conflict of interest

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