Florey Institute for Neuroscience and Mental Health, University of Melbourne, Australia.
School of Psychology and Public Health, La Trobe University, Melbourne, Australia.
Brain Res. 2021 Jul 1;1762:147428. doi: 10.1016/j.brainres.2021.147428. Epub 2021 Mar 15.
To assess the long-term effects of chronic adolescent methamphetamine (METH) treatment on the serotonin system in the brain, we used serotonin-1A receptor (5-HT) and serotonin transporter (SERT) autoradiography, and quantitative tryptophan-hydroxylase 2 (TPH2) immunohistochemistry in the raphe nuclei of mice. Because of the modulatory role of brain-derived neurotrophic factor (BDNF) on the serotonin system and the effects of METH, we included both BDNF heterozygous (HET) mice and wildtype (WT) controls. Male and female mice of both genotypes were treated with an escalating METH dose regimen from the age of 6-9 weeks. At least two weeks later, acute locomotor hyperactivity induced by a 5 mg/kg D-amphetamine challenge was significantly enhanced in METH-pretreated mice, showing long-term sensitisation. METH pretreatment caused a small, but significant decrease of 5-HT receptor binding in the dorsal raphe nucleus (DRN) of males independent of genotype, but there were no changes in the median raphe nucleus (MRN) or in SERT binding density. METH treatment reduced the number of TPH2 positive cells in ventral subregions of the rostral and medial DRN independent of genotype. METH treatment selectively reduced DRN cell counts in BDNF HET mice compared to wildtype mice in medial and caudal ventrolateral subregions previously associated with panic-like behaviour. The data increase our understanding of the long-term and selective effects of METH on brain serotonin systems. These findings could be relevant for some of the psychosis-like symptoms associated with long-term METH use.
为了评估慢性青少年甲基苯丙胺（METH）治疗对大脑中 5-羟色胺 1A 受体（5-HT1A）和 5-羟色胺转运体（SERT）的长期影响，我们使用 5-羟色胺能核（raphe nuclei）中的 5-羟色胺 1A 受体（5-HT1A）和 5-羟色胺转运体（SERT）放射性自显影技术，以及定量色氨酸羟化酶 2（TPH2）免疫组织化学方法，对小鼠进行了研究。由于脑源性神经营养因子（BDNF）对 5-羟色胺系统的调节作用以及 METH 的作用，我们同时包括了 BDNF 杂合子（HET）小鼠和野生型（WT）对照。雄性和雌性的两种基因型的小鼠均从 6-9 周龄开始接受递增的 METH 剂量方案治疗。至少两周后，5 毫克/公斤 D-苯丙胺挑战引起的急性运动过度活跃在 METH 预处理的小鼠中显著增强，表现出长期敏感化。METH 预处理导致雄性小鼠背侧中缝核（DRN）中的 5-HT 受体结合减少，尽管有轻微的减少，但与基因型无关，但在中缝核（MRN）或 SERT 结合密度中没有变化。METH 处理减少了腹侧中缝核（DRN）中 TPH2 阳性细胞的数量，这与基因型无关。与野生型小鼠相比，METH 处理选择性地减少了 BDNF HET 小鼠中背侧中缝核（DRN）的细胞计数，特别是在与惊恐样行为相关的中缝核（DRN）内侧和尾侧腹外侧亚区。这些数据增加了我们对 METH 对大脑 5-羟色胺系统的长期和选择性影响的理解。这些发现可能与长期使用 METH 相关的一些精神病样症状有关。
