Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.
This rat study (n=36) investigated the effects of ibogaine (0, 20, 40 mg/kg) in rats and found that higher doses promoted the expression of Glial cell Derived Neurotrophic Factor (GDNF) and that both doses promoted proBDNF expression in the Nucleus Accumbens, which may be underlying mediators of its long-lasting effect on reducing drug dependence.
Authors
- Deborah Mash
- Dalibor Sames
- Ignacio Carrera
Published
Abstract
Introduction
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.
Methods
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.
Results
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.
Research Summary of 'Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.'
Introduction
Ibogaine is an indole alkaloid traditionally used as a psychedelic and has attracted scientific interest because uncontrolled clinical observations and animal studies report reductions in craving and self-administration for several drugs of abuse after single large doses. Earlier preclinical work suggested that ibogaine’s long-lasting anti-addictive effects may be mediated in part by increased Glial Cell Derived Neurotrophic Factor (GDNF) in the midbrain, particularly the Ventral Tegmental Area (VTA). However, there had been no systematic study comparing ibogaine’s effects on the expression of multiple neurotrophic factors across distinct dopaminergic regions that form the mesocorticolimbic and nigrostriatal circuits. Lason and colleagues set out to characterise how a single intraperitoneal (i.p.) administration of ibogaine alters mRNA and protein levels of three neurotrophic factors — GDNF, Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) — in four brain regions relevant to dopaminergic neurotransmission: the VTA, prefrontal cortex (PFC), nucleus accumbens (NAcc) and substantia nigra (SN). They tested two doses (20 mg/kg and 40 mg/kg) and examined outcomes at two time points (3 h and 24 h) chosen to separate acute drug/metabolite presence from longer-lasting molecular changes; locomotor behaviour in an open field was recorded at the same time points. This single‑dose, time‑course approach aimed to identify site‑ and dose‑specific patterns of neurotrophic factor regulation that could plausibly link ibogaine administration to the long‑lasting behavioural effects reported in addiction models, and to explore whether changes in mRNA were echoed by changes in mature protein or precursor forms such as proBDNF.
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Study Details
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- APA Citation
Marton, S., González, B., Rodríguez-Bottero, S., Miquel, E., Martínez-Palma, L., Pazos, M., Prieto, J. P., Rodríguez, P., Sames, D., Seoane, G., Scorza, C., Cassina, P., & Carrera, I. (2019). Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00193
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