Marton Soledad, González Bruno, Rodríguez-Bottero Sebastián, Miquel Ernesto, Martínez-Palma Laura, Pazos Mariana, Prieto José Pedro, Rodríguez Paola, Sames Dalibor, Seoane Gustavo, Scorza Cecilia, Cassina Patricia, Carrera Ignacio
Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Front Pharmacol. 2019 Mar 5;10:193. doi: 10.3389/fphar.2019.00193. eCollection 2019.
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 (I), 40 mg/kg (I) 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 I, 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 I. Finally, NGF mRNA was upregulated in all regions after I, while I showed a selective upregulation in PFC and VTA. Regarding protein levels, an increase of GDNF was observed in the VTA only for I 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 I but not for I 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.
伊博格碱是一种非典型的致幻生物碱，因其据报道具有减弱觅药行为的能力而成为研究对象。最近的研究表明，伊博格碱对大鼠酒精自我给药的影响与腹侧被盖区（VTA）中胶质细胞源性神经营养因子（GDNF）的释放有关，腹侧被盖区是一个中脑区域，含有多巴胺能神经元的胞体。尽管先前的报道显示伊博格碱能够诱导大鼠中脑GDNF的表达，但尚无研究探讨其对含有多巴胺能神经元的不同脑区中GDNF以及其他神经营养因子（NFs）如脑源性神经营养因子（BDNF）或神经生长因子（NGF）表达的影响。在这项研究中，我们检测了急性给予伊博格碱对VTA、前额叶皮质（PFC）、伏隔核（NAcc）和黑质（SN）中这些NFs表达的影响。大鼠腹腔注射20mg/kg（I组）、40mg/kg（I组）的伊博格碱或溶剂，在3小时和24小时后分析NFs的表达。在24小时时，观察到NFs转录本的表达呈位点和剂量依赖性增加。仅对于I组，GDNF在VTA和SN中被选择性上调。两个剂量均引起NAcc、SN和PFC中BDNF转录本表达的大幅增加，而在VTA中仅I组有显著影响。最后，I组给药后所有区域的NGF mRNA均上调，而I组在PFC和VTA中表现出选择性上调。关于蛋白水平，仅I组的VTA中观察到GDNF增加，但在所有研究区域中BDNF均未发现显著增加。有趣的是，两个剂量的NAcc中均检测到前体BDNF增加。这些结果首次表明，给药24小时后，仅I组的VTA中GDNF有选择性增加，而I组没有，这与先前在啮齿动物自我给药研究中发现的有效剂量一致。需要进一步研究以了解这些变化对伊博格碱减弱觅药行为能力的贡献。
