The Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
The Pennsylvania State University College of Medicine, Department of Neural and Behavioral Sciences, 500 University Drive, Hershey, PA 17033, United States of America.
Neurotoxicol Teratol. 2024 Sep-Oct;105:107385. doi: 10.1016/j.ntt.2024.107385. Epub 2024 Aug 23.
Opioid use during pregnancy and subsequent neonatal opioid withdrawal syndrome (NOWS) have been associated with poor developmental outcomes including cognitive functioning. Less is known about the underlying molecular effects of prenatal opioid exposure and subsequent withdrawal; however, given the recent increase in NOWS cases, there is a pressing need to better understand these effects, which may partially explain cognitive deficits that have been observed in both preclinical NOWS models and patients with NOWS. This study evaluated the effects of prenatal heroin exposure and subsequent precipitated withdrawal symptoms on microglial reactivity in the nucleus accumbens (NAc), dorsal hippocampus (HC), and ventral tegmental area (VTA) in rat neonates, as well as cognitive functioning at three developmental time points using the Morris Water Maze (MWM) task.
Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams via osmotic minipump. A total of 63 rat neonates underwent naloxone-precipitated (5 mg/kg, subcutaneous injection) withdrawal testing at postnatal day 10 (PN10). Following withdrawal testing, neonates were randomly assigned to undergo perfusion and subsequent immunohistochemistry experiments to fluoresce Iba-1 for microglia detection, or to undergo the MWM task at three separate developmental time points (PN21-23; PN37; PN60) for cognitive testing.
Results suggest that in-utero heroin exposure led to an increase in ultrasonic vocalizations during naloxone-precipitated withdrawal; a sensitive index of withdrawal in rat neonates. Additional results suggest increased microglial reactivity in the HC and VTA, but not the NAc, as well as reduced performance during the MWM in the group exposed to heroin in-utero.
Together, these data suggest that in-utero opioid exposure is associated with microglial reactivity in brain regions associated with learning and memory, and may be associated with later cognitive deficits. Further research is needed to characterize these findings, which may inform future therapeutic strategies for this vulnerable population.
孕期使用阿片类药物以及随后的新生儿阿片戒断综合征（NOWS）与认知功能等不良发育结果相关。然而，对于产前阿片类药物暴露和随后戒断的潜在分子影响知之甚少；但是，鉴于 NOWS 病例的近期增加，迫切需要更好地了解这些影响，这可能部分解释了在临床前 NOWS 模型和 NOWS 患者中观察到的认知缺陷。本研究评估了产前海洛因暴露和随后戒断症状对新生大鼠伏隔核（NAc）、背海马（HC）和腹侧被盖区（VTA）中小胶质细胞反应的影响，以及使用 Morris 水迷宫（MWM）任务在三个发育时间点的认知功能。
通过渗透微型泵随机分配并向六只怀孕的 Sprague Dawley 大鼠给予海洛因或生理盐水（2mg/kg）。63 只新生大鼠在出生后第 10 天（PN10）接受纳洛酮诱发的戒断测试（5mg/kg，皮下注射）。戒断测试后，新生大鼠随机分为两组进行灌注和随后的免疫组织化学实验，以检测小胶质细胞的荧光 Iba-1，或在三个不同的发育时间点（PN21-23；PN37；PN60）进行 MWM 任务，以进行认知测试。
结果表明，宫内海洛因暴露导致纳洛酮诱发戒断期间超声发声增加；这是大鼠新生仔中戒断的敏感指标。此外的结果表明，HC 和 VTA 中的小胶质细胞反应增加，但 NAc 中没有，并且在宫内暴露于海洛因的组中在 MWM 中的表现降低。
总的来说，这些数据表明，宫内阿片类药物暴露与与学习和记忆相关的大脑区域中小胶质细胞的反应有关，并且可能与以后的认知缺陷有关。需要进一步研究来描述这些发现，这可能为这一脆弱人群的未来治疗策略提供信息。
