Department of Pediatrics, E-DA Hospital, Kaohsiung, Taiwan.
School of Medicine, I-Shou University, Kaohsiung, Taiwan.
Biomed Res Int. 2018 Jun 10;2018:5437092. doi: 10.1155/2018/5437092. eCollection 2018.
Prenatal exposure to morphine causes altered glutamatergic neurotransmission, which plays an important pathophysiological role for neurobiological basis of opiate-mediated behaviors in such offspring. However, it is still not clear whether such alteration involves gene expression of ionotropic glutamate receptor subunits. In this study, we further studied whether prenatal morphine exposure resulted in long-term changes in the gene expression of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, -methyl-d-aspartate (NMDA) receptor, and postsynaptic density 95 in the mesocorticolimbic area (an essential integration circuitry for drug craving behavior), nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC), of rat offspring from morphine-addicted mothers. Experimental results showed that prenatal morphine exposure led to a persistent downregulation of gene expression in the AMPA and NMDA receptor subunit, with a differential manner of decreased magnitudes, at the age of postnatal days 14 (P14) and P30. However, in PFC, the gene expression of the AMPA receptor subunit was not synchronized in observed rat offspring subjected to prenatal morphine exposure. An upregulation of gene expression in the AMPA receptor subunit 3 (GluR3) was persistently observed at P14 and P30. Furthermore, the gene expressions of PSD-95 in NAc, VTA, and PFC were all decreased concurrently. Collectively, the results suggest that prenatal exposure to morphine may initiate molecular mechanisms leading to a long-lasting, differential alteration in gene expression of the inotropic glutamate receptor subunit and PSD-95 in the mesocorticolimbic circuitry in rat offspring. This study raises a possibility in which differential changes in gene expression with a long-lasting manner may play a role for the development of nearly permanent changes in opiate-mediated behaviors, at least in part for the neurobiological pathogenesis in offspring.
产前暴露于吗啡会导致谷氨酸能神经传递改变，这对于阿片类药物介导的行为的神经生物学基础起着重要的病理生理作用。然而，目前尚不清楚这种改变是否涉及离子型谷氨酸受体亚基的基因表达。在这项研究中，我们进一步研究了产前吗啡暴露是否会导致中脑边缘区（药物渴求行为的重要整合电路）、伏隔核（NAc）、腹侧被盖区（VTA）和前额叶皮质（PFC）中 - 氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体、 - 甲基-D-天冬氨酸（NMDA）受体和突触后密度 95 的基因表达长期改变，这些是吗啡成瘾母亲的大鼠后代。实验结果表明，产前吗啡暴露导致 AMPA 和 NMDA 受体亚基的基因表达持续下调，在出生后第 14 天（P14）和第 30 天（P30）时以不同的幅度降低。然而，在 PFC 中，观察到的产前吗啡暴露的大鼠后代的 AMPA 受体亚基基因表达没有同步。在 P14 和 P30 时，AMPA 受体亚基 3（GluR3）的基因表达持续上调。此外，NAc、VTA 和 PFC 中的 PSD-95 基因表达均同时降低。总之，这些结果表明，产前暴露于吗啡可能引发分子机制，导致中脑边缘区电路中离子型谷氨酸受体亚基和 PSD-95 的基因表达长期、差异改变。这项研究提出了一种可能性，即具有持久方式的基因表达差异变化可能在阿片类药物介导的行为的永久性改变的发展中起作用，至少在一定程度上是后代神经生物学发病机制的原因。
