Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.

Ignacio Carrera,Dalibor Sames,Mariana Pazos,Ernesto Miquel,Laura Martínez-Palma,Bruno González,José Pedro Prieto,Soledad Marton,Cecilia Scorza,Paola Rodríguez,Patricia Cassina,Sebastián Rodríguez-Bottero,Gustavo Seoane

doi:10.3389/fphar.2019.00193

Abstract

Ibogaine is an atypical psychedelic alkaloid, which has been subject of research due to its reported ability to attenuate drug-seeking behavior. Recent work has suggested that ibogaine effects on alcohol self-administration in rats are related to the release of Glial cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts the soma of dopaminergic neurons. Although previous reports have shown ibogaine’s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF and other neurotrophic factors (NFs) such as Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct brain regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 h. At 24 h an increase of the expression of the NFs transcripts was observed in a site and dose dependent manner. Only for I40, GDNF was selectively upregulated in the VTA and SN. Both doses elicited a large increase in the expression of BDNF transcripts in the NAcc, SN and PFC, while in the VTA a significant effect was found only for I40. Finally, NGF mRNA was upregulated in all regions after I40, while I20 showed a selective upregulation in PFC and VTA. Regarding protein levels, an increase of GDNF was observed in the VTA only for I40 but no significant increase for BDNF was found in all the studied areas. Interestingly, an increase of proBDNF was detected in the NAcc for both doses. These results show for the first time a selective increase of GDNF specifically in the VTA for I40 but not for I20 after 24 h of administration, which agrees with the effective dose found in previous self-administration studies in rodents. Further research is needed to understand the contribution of these changes to ibogaine’s ability to attenuate drug-seeking behavior.

Highlights

Ibogaine is the main indole alkaloid isolated from the root bark of the African shrub Tabernanthe iboga (Lavaud and Massiot, 2017)
This finding is important since the ability of ibogaine to attenuate ethanol self-administration had previously been proposed to be mediated, at least in part, by the increase in Glial cell Derived Neurotrophic Factor (GDNF) content in the Ventral Tegmental Area (VTA). (He et al, 2005; He and Ron, 2006) we show that ibogaine 20 mg/kg (I20) administration does not increase GDNF expression in any of the studied brain areas, which is in accordance with the observation that this dose was not effective in reducing drug self-administration in the majority of previous studies in rodents (Glick et al, 1991, 1994; Cappendijk and Dzoljic, 1993; Dworkin et al, 1995)
This study demonstrates for the first time that ibogaine administration simultaneously alters the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF), and Nerve Growth Factor (NGF) transcripts in rat brain regions related to the dopamine neurotransmission in a dose- and time-dependent manner

Summary

Introduction

Ibogaine is the main indole alkaloid isolated from the root bark of the African shrub Tabernanthe iboga (Lavaud and Massiot, 2017). Ibogaine binds to numerous central nervous system (CNS) targets at the micromolar range such as: nicotinic acetylcholine receptors (nAChR α3β4 and α2β4) (Fryer and Lukas, 1999; Arias et al, 2010, 2015), N-methyl-D-aspartate (NMDA) (Mash et al, 1995b), kappa and mu opioid (Antonio et al, 2013; Maillet et al, 2015), 5HT2A and 5HT3 receptors (Glick et al, 2000) and the dopamine and serotonin transporters (Mash et al, 1995a; Glick et al, 2001; Asjad et al, 2017) These ibogaine-receptor interactions do not seem to account for the long-lasting effects of ibogaine found in rodents which are described to last for 48 to 72 h after ibogaine administration (Glick et al, 1991, 1994; Cappendijk and Dzoljic, 1993). No appreciable amounts of noribogaine have been found in rodents’ brain tissue 19 h after ibogaine intraperitoneal (i.p.) administration (Pearl et al, 1997), and only approximately 5% of the noribogaine Cmax was detected in serum 24 h after the same treatment (Baumann et al, 2001b)

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