Department of Neuroscience, The Scripps Research Institute,USA.
Department of Neuroscience, The Scripps Research Institute,USA; VA San Diego Healthcare System, USA; Department of Anesthesiology, University of California San Diego, San Diego, CA, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jul 13;85:46-53. doi: 10.1016/j.pnpbp.2018.03.023. Epub 2018 Mar 28.
The detrimental effects of amphetamines on developmental stages of NPCs are limited to rodent brain and it is not known if these effects occur in nonhuman primates which are the focus of the current investigation. Young adult rhesus macaques either experienced MDMA only, a combination of amphetamines (MDMA, MDA and methamphetamine) or no amphetamines (controls) and hippocampal tissue was processed for immunohistochemical analysis.Quantitative stereological analysis showed that intermittent exposure to MDMA or the three amphetamines over 9.6 months causes >80% decrease in the number of Ki-67 cells (actively dividing NPCs) and >50% decrease in the number of NeuroD1 cells (NPCs that have attained a neuronal phenotype). Co-labeling analysis revealed distinct, actively dividing hippocampal NPCs in the subgranular zone of the dentate gyrus that were in transition from stem-like radial glia-like cells (type-1) to immature transiently amplifying neuroblasts (type-2a, type-2b, and type-3).MDMA-alone and the combination reduced the number of dividing type-1 and type-3 NPCs and cells that were not NPCs. These data indicate that amphetamines interfere with the division and migration of NPCs. Notably, the reduction in the number of NPCs and immature neurons were not associated with changes in cell death (via apoptosis) or granule cell neuron numbers, indicating that amphetamines selectively affected the generation and maturation of newly born granule cell neurons. In sum, our findings suggest that alterations in the cellular composition in the dentate gyrus during chronic exposure to amphetamines can effect neuroplasticity in the hippocampus and influence functional properties of hippocampal neurons.
安非他命对 NPC 发育阶段的有害影响仅限于啮齿动物大脑，目前还不知道这些影响是否会发生在非人类灵长类动物身上，而非人类灵长类动物是当前研究的重点。年轻成年恒河猴要么只经历 MDMA，要么经历 MDMA 与安非他命（MDMA、MDA 和甲基苯丙胺）的组合，要么不经历安非他命（对照组），然后对海马组织进行免疫组织化学分析。定量立体学分析显示，间歇性暴露于 MDMA 或这三种安非他命超过 9.6 个月会导致 Ki-67 细胞（活跃分裂的 NPC）数量减少超过 80%，NeuroD1 细胞（已获得神经元表型的 NPC）数量减少超过 50%。共标记分析显示，在齿状回颗粒下区有独特的、活跃分裂的海马 NPC，它们正在从干细胞样放射状胶质样细胞（1 型）向不成熟的短暂扩增神经母细胞（2a 型、2b 型和 3 型）转变。MDMA 单独和组合减少了分裂的 1 型和 3 型 NPC 以及非 NPC 的数量。这些数据表明安非他命干扰 NPC 的分裂和迁移。值得注意的是，NPC 数量和不成熟神经元的减少与细胞死亡（通过细胞凋亡）或颗粒细胞神经元数量的变化无关，这表明安非他命选择性地影响新生颗粒细胞神经元的产生和成熟。总之，我们的研究结果表明，在慢性暴露于安非他命期间，齿状回细胞组成的改变可能会影响海马体的神经可塑性，并影响海马体神经元的功能特性。
