Sara L. Mills-Huffnagle , Charles N. Zawatsky , Gjhvona Bryant , Michael Ebert , Corinne M. Augusto , Ann Sipe , Nelli Horvath , Jennifer E. Nyland
{"title":"胎儿期连续接触低剂量海洛因的大鼠在戒断症状、小胶质细胞活性和认知功能方面的差异。","authors":"Sara L. Mills-Huffnagle , Charles N. Zawatsky , Gjhvona Bryant , Michael Ebert , Corinne M. Augusto , Ann Sipe , Nelli Horvath , Jennifer E. Nyland","doi":"10.1016/j.ntt.2024.107385","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>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.</p></div><div><h3>Methods</h3><p>Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams <em>via</em> 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.</p></div><div><h3>Results</h3><p>Results suggest that <em>in-utero</em> 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 <em>in-utero</em>.</p></div><div><h3>Discussion</h3><p>Together, these data suggest that <em>in-utero</em> 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.</p></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"105 ","pages":"Article 107385"},"PeriodicalIF":2.6000,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Differences in withdrawal symptoms, microglia activity, and cognitive functioning in rats exposed to continuous low-dose heroin in-utero\",\"authors\":\"Sara L. Mills-Huffnagle , Charles N. Zawatsky , Gjhvona Bryant , Michael Ebert , Corinne M. Augusto , Ann Sipe , Nelli Horvath , Jennifer E. Nyland\",\"doi\":\"10.1016/j.ntt.2024.107385\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>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.</p></div><div><h3>Methods</h3><p>Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams <em>via</em> 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.</p></div><div><h3>Results</h3><p>Results suggest that <em>in-utero</em> 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 <em>in-utero</em>.</p></div><div><h3>Discussion</h3><p>Together, these data suggest that <em>in-utero</em> 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.</p></div>\",\"PeriodicalId\":19144,\"journal\":{\"name\":\"Neurotoxicology and teratology\",\"volume\":\"105 \",\"pages\":\"Article 107385\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2024-08-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurotoxicology and teratology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0892036224000679\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurotoxicology and teratology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0892036224000679","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Differences in withdrawal symptoms, microglia activity, and cognitive functioning in rats exposed to continuous low-dose heroin in-utero
Introduction
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.
Methods
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
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.
Discussion
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.
期刊介绍：
Neurotoxicology and Teratology provides a forum for publishing new information regarding the effects of chemical and physical agents on the developing, adult or aging nervous system. In this context, the fields of neurotoxicology and teratology include studies of agent-induced alterations of nervous system function, with a focus on behavioral outcomes and their underlying physiological and neurochemical mechanisms. The Journal publishes original, peer-reviewed Research Reports of experimental, clinical, and epidemiological studies that address the neurotoxicity and/or functional teratology of pesticides, solvents, heavy metals, nanomaterials, organometals, industrial compounds, mixtures, drugs of abuse, pharmaceuticals, animal and plant toxins, atmospheric reaction products, and physical agents such as radiation and noise. These reports include traditional mammalian neurotoxicology experiments, human studies, studies using non-mammalian animal models, and mechanistic studies in vivo or in vitro. Special Issues, Reviews, Commentaries, Meeting Reports, and Symposium Papers provide timely updates on areas that have reached a critical point of synthesis, on aspects of a scientific field undergoing rapid change, or on areas that present special methodological or interpretive problems. Theoretical Articles address concepts and potential mechanisms underlying actions of agents of interest in the nervous system. The Journal also publishes Brief Communications that concisely describe a new method, technique, apparatus, or experimental result.
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