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submitted on 18.03.2020 and posted on 19.03.2020by 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