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

Soledad Marton^1†, Bruno González^2†, Sebastián Rodríguez-Bottero¹, Ernesto Miquel¹, Laura Martínez-Palma¹, Mariana Pazos², José Pedro Prieto³, Paola Rodríguez², Dalibor Sames⁴, Gustavo Seoane², Cecilia Scorza^3*, Patricia Cassina^1* and Ignacio Carrera^2*

• ¹Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
• ²Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay
• ³Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
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• ⁴Department of Chemistry, Columbia University, New York, NY, United States
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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.

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Introduction

Ibogaine is the main indole alkaloid isolated from the root bark of the African shrub Tabernanthe iboga (Lavaud and Massiot, 2017). Traditionally used in African religious ceremonies as a psychedelic, ibogaine became a subject of interest to the scientific community due to its reported ability to reduce craving and self-administration of several drugs of abuse in humans (Brown, 2013). These effects found mainly in uncontrolled clinical trials and observational studies, have been reported to be long-lasting enduring weeks to months after a single administration of large doses of ibogaine (Schenberg et al., 2014; Brown and Alper, 2017; Noller et al., 2017; Corkery, 2018; Malcolm et al., 2018; Mash et al., 2018). In animal models for drug dependence, ibogaine also reduces the self-administration of morphine and heroin (Glick et al., 1991, 1994; Dworkin et al., 1995), cocaine (Cappendijk and Dzoljic, 1993; Glick et al., 1994), and alcohol (He et al., 2005), with long-lasting effects that persists beyond pharmacokinetic elimination of the drug (Alper, 2001). In addition, ibogaine administration to animals also reduces naloxone or naltrexone precipitated-withdrawal signs (Dzoljic et al., 1988; Glick et al., 1992; Leal et al., 2003).

Although a vast amount of research has been done regarding the pharmacology of ibogaine, the mechanism of action of its ability to attenuate drug-seeking behavior remains unresolved (Alper, 2001; Maciulaitis et al., 2008; Brown, 2013). 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), 5HT_2A 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). However, 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). In rodents, ibogaine has a short half-life of 1–2 h raising the hypothesis that its longer-lived active metabolite, noribogaine, could be responsible for the enduring effects elicited by ibogaine. Both, the parent drug and its metabolite have differences in their binding profiles and affinities to the abovementioned CNS receptors (Staley et al., 1996). However, 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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A few years ago, a novel hypothesis linking ibogaine’s attenuation of alcohol self-administration in rodents to its ability to modulate the expression of Glial Cell Derived Neurotrophic Factor (GDNF) in the brain was proposed. It was shown that a single ibogaine i.p. administration (40 mg/kg) increased the expression of GDNF in the midbrain of rats and mice for up to 24 h (He et al., 2005). In addition, microinjection of ibogaine into the Ventral Tegmental Area (VTA), produced a long-lasting reduction of ethanol self-administration, a response that was attenuated by the intra-VTA delivery of anti-GDNF neutralizing antibodies. These results suggested that ibogaine mediates its effects against ethanol consumption by increasing GDNF content in the VTA (He et al., 2005). Accordingly, another study from the same research group showed that the intra-VTA infusion of noribogaine induced a long-lasting decrease in ethanol self-administration (Carnicella et al., 2010). Further, ibogaine-derived synthetic derivatives were recently shown to induce the release of GDNF in vitro, in established cell line systems (Gassaway et al., 2016). These observations formed the basis for a new rationale to explain the long-lasting effects of ibogaine; i.e., the induction of GDNF by ibogaine/noribogaine may activate an autocrine loop, leading a long-term synthesis and release of GDNF (that persists beyond elimination of both substances). This mechanism may reverse the biochemical adaptations to chronic exposure to drugs of abuse in the reward system (He and Ron, 2006).

Neurotrophic Factors (NFs), such as GDNF and BDNF (Brain Derived Neurotrophic Factor) are small proteins that promote the growth, differentiation, synaptogenesis, and survival of neurons. Their expression in the nervous tissue is relatively high during the development of the CNS, where substantial growth, differentiation and remodeling of the nervous system occur (Barde, 1990; Lu and Figurov, 1997). More recently, it has been discovered that NFs play important roles in the adult brain where they modulate maintenance, protection, repair and plasticity of the nervous tissue (Reichardt, 2006; Schmidt and Duman, 2007). Furthermore, accumulating evidence has suggested that GDNF and BDNF mediate neuronal remodeling processes that occur during the development of substance use disorders (SUDs) (Bolaños and Nestler, 2004; McGough et al., 2004; Angelucci et al., 2007; Jeanblanc et al., 2009; Bie et al., 2012). Particularly, the role of GDNF and BDNF in the neuroadaptations in the mesocorticolimbic dopamine system (Prefrontal Cortex, PFC- VTA-Nucleus Accumbens, NAcc pathway) induced by repeated exposure to drugs of abuse has been extensively studied, including the impact of manipulating NFs levels on drug-seeking behavior in animal models (Russo et al., 2009; Ghitza et al., 2010; Koskela et al., 2017). It has been shown that the administration of BDNF or GDNF can either promote or inhibit drug-taking behaviors depending mainly on the brain site of administration, along with other several factors such as the drug type, the addiction phase (initiation, maintenance, abstinence or relapse), the time interval between site-specific NFs injections and the related behavioral assessments (Ghitza et al., 2010). For example, BDNF infusion into the NAcc increases cocaine-seeking behavior (Graham et al., 2007), while BDNF infusion into the medial pre-frontal cortex (mPFC) suppresses it (Berglind et al., 2007). Additionally, infusion of BDNF into the dorsolateral striatum decreases ethanol self-administration in rats (Jeanblanc et al., 2009).

Given the importance and the site-specificity of the elicited responses, we decided to analyze the effect of a single administration of ibogaine on the expression of GDNF and BDNF (mRNA transcripts and protein content) at two time points in those brain areas which define the mesocorticolimbic dopamine system such as VTA, PFC and NAcc (Figure 1). As the Substantia Nigra (SN) is a major nucleus of dopaminergic neurons important in the basal ganglia functioning, the expression of these NFs in this region was also studied. In order to examine the impact of ibogaine administration on the expression of other relevant NFs (which impact on drug-seeking behaviors has been much less studied) the Nerve Growth Factor (NGF) transcript content was also analyzed in the abovementioned brain areas. Selected time points were chosen considering previous pharmacokinetics reports in rats using i.p. administration (Pearl et al., 1997; Zubaran et al., 1999; Baumann et al., 2001a,b). In this manner, we chose to study NFs expression/content in the selected brain areas at 3 h, where ibogaine and noribogaine are present in relevant concentrations (Baumann et al., 2001b), and at 24 h where ibogaine is no longer detected and no significant amounts of noribogaine would be present in the brain (Pearl et al., 1997). In this manner, is expected that the observed effects found at 24 h, would be due to long lasting mechanisms elicited by the drug which remain after it has been cleared from the brain, but not from the acute effects of ibogaine/noribogaine. Finally, a behavioral study recording the locomotor activity of the control and drug-treated animals was performed using an open field test for each time point.

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