PET imaging of dopamine release in the frontal cortex of manganese-exposed non-human primates
PET imaging of dopamine release in the frontal cortex of manganese-exposed non-human primates
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DOI：
10.1111/jnc.14681
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发表时间：
2019-07-01
影响因子：
4.7
通讯作者：
Schneider, Jay S.
中科院分区：
文献类型：
--
作者：
Guilarte, Tomas R.;Yeh, Chien-Lin;Schneider, Jay S.
暴露于过量锰（Mn）的人类和非人类灵长类动物表现出工作记忆和注意力的缺陷。额叶皮层和额纹状体网络与工作记忆有关，这些回路依赖多巴胺来实现最佳表现。在这里，我们的目的是确定慢性锰暴露是否会改变非人灵长类动物额叶皮层的体内多巴胺释放（DAR）。我们使用[C-11]-FLB457正电子发射断层扫描和安非他明激发来测量食蟹猴的DAR。在Mn暴露前（基线）、Mn暴露期间的不同时间点以及停止Mn暴露10个月后，动物接受了[C-11]-FLB457正电子发射断层扫描，有安非他明刺激和没有安非他明刺激。与基线相比，6只暴露于锰的动物中有4只表现出显著的额皮质DAR损伤。一只Mn动物的DAR没有变化，另一只Mn动物的DAR相对于基线升高。在逆转研究中，一只暴露于锰的动物DAR完全恢复，而另一只动物部分恢复。在这两种动物中，基于t1加权磁共振成像，在停止暴露10个月后，额叶皮质Mn浓度恢复正常。额叶皮质组织d1 -多巴胺受体（D1R）放射自显影显示，停止Mn暴露的Mn动物表达的D1R水平比未停止Mn暴露的Mn动物或对照动物低约50%。本研究提供的证据表明，锰暴露受试者的额叶皮层DAR和D1R的改变可能与工作记忆和注意力缺陷有关。
Humans and non-human primates exposed to excess levels of manganese (Mn) exhibit deficits in working memory and attention. Frontal cortex and fronto-striatal networks are implicated in working memory and these circuits rely on dopamine for optimal performance. Here, we aimed to determine if chronic Mn exposure alters in vivo dopamine release (DAR) in the frontal cortex of non-human primates. We used [C-11]-FLB457 positron emission tomography with amphetamine challenge to measure DAR in Cynomolgus macaques. Animals received [C-11]-FLB457 positron emission tomography scans with and without amphetamine challenge prior to Mn exposure (baseline), at different time points during the Mn exposure period, and after 10 months of Mn exposure cessation. Four of six Mn-exposed animals expressed significant impairment of frontal cortex in vivo DAR relative to baseline. One Mn animal had no change in DAR and another Mn animal expressed increased DAR relative to baseline. In the reversal studies, one Mn-exposed animal exhibited complete recovery of DAR while the second animal had partial recovery. In both animals, frontal cortex Mn concentrations normalized after 10 months of exposure cessation based on T1-weighted magnetic resonance imaging. D1-dopamine receptor (D1R) autoradiography in frontal cortex tissue indicates that Mn animals that experienced cessation of Mn exposure expressed D1R levels that were approximately 50% lower than Mn animals that did not experience cessation of Mn exposure or control animals. The present study provides evidence of Mn-induced alterations in frontal cortex DAR and D1R that may be associated with working memory and attention deficits observed in Mn-exposed subjects.