Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA.
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Int J Mol Sci. 2023 Aug 23;24(17):13092. doi: 10.3390/ijms241713092.
The dopamine transporter (DAT) is an integral member of the dopaminergic system and is responsible for the release and reuptake of dopamine from the synaptic space into the dopaminergic neurons. DAT is also the major target of amphetamine (Amph). The effects of Amph on DAT have been intensively studied; however, the mechanisms underlying the long-term effects caused by embryonal exposure to addictive doses of Amph remain largely unexplored. As in mammals, in the nematode Amph causes changes in locomotion which are largely mediated by the DAT homologue, DAT-1. Here, we show that chronic embryonic exposures to Amph alter the expression of DAT-1 in adult via long-lasting epigenetic modifications. These changes are correlated with an enhanced behavioral response to Amph in adult animals. Importantly, pharmacological and genetic intervention directed at preventing the Amph-induced epigenetic modifications occurring during embryogenesis inhibited the long-lasting behavioral effects observed in adult animals. Because many components of the dopaminergic system, as well as epigenetic mechanisms, are highly conserved between and mammals, these results could be critical for our understanding of how drugs of abuse initiate predisposition to addiction.
多巴胺转运体（DAT）是多巴胺能系统的一个组成部分，负责将多巴胺从突触间隙释放并重新摄取到多巴胺能神经元中。DAT 也是安非他命（Amph）的主要靶点。安非他命对 DAT 的影响已经得到了深入研究；然而，胚胎暴露于成瘾剂量的安非他命所导致的长期影响的机制在很大程度上仍未得到探索。与哺乳动物一样，在线虫中，Amph 会引起运动的变化，这些变化主要是由 DAT 同源物 DAT-1 介导的。在这里，我们表明，慢性胚胎暴露于 Amph 会通过持久的表观遗传修饰改变成年动物中 DAT-1 的表达。这些变化与成年动物对 Amph 的行为反应增强有关。重要的是，针对预防胚胎发生期间 Amph 诱导的表观遗传修饰的药理学和遗传学干预，抑制了在成年动物中观察到的持久的行为效应。由于多巴胺能系统的许多成分以及表观遗传机制在 和哺乳动物之间高度保守，这些结果对于我们理解滥用药物如何引发成瘾易感性可能至关重要。
