Brain, Behavior & the Environment Program, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, United States; Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, United States.
Department of Biostatistics, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, United States.
Neurotoxicology. 2021 Jan;82:119-129. doi: 10.1016/j.neuro.2020.11.008. Epub 2020 Nov 25.
Childhood lead (Pb) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb exposure (1500 ppm in the diet) on μ-opioid receptor (MOR) levels in the rat brain using [H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats. Our results indicate that chronic developmental Pb exposure increases the levels of [H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb-exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb-exposed adult male rats (PN120). Specifically, at PN14, Pb-exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb-exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb-exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb-exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb-exposed males in the medial thalamus. Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb, an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse.
儿童铅（Pb）中毒是一个全球性的公共卫生问题，其主要特征是学习和学业成绩下降。人类和临床前研究表明，儿童 Pb 中毒与物质滥用和犯罪行为倾向之间存在关联。虽然环境因素已被认为与阿片类药物成瘾有关，但对于接触环境污染物对大脑阿片系统的影响知之甚少。阿片受体参与阿片类药物和其他滥用药物的生物学效应。在这项研究中，我们使用 [H]-D-Ala2-MePhe4-Gly-ol5 内啡肽 ([H]-DAMGO) 定量受体放射自显影术，在雄性和雌性大鼠的不同发育阶段（幼年期、早期青春期、晚期青春期和成年期），研究慢性发育性 Pb 暴露（饮食中 1500ppm）对大鼠大脑 μ-阿片受体（MOR）水平的影响。我们的结果表明，慢性发育性 Pb 暴露会增加幼年期和早期青春期 Pb 暴露雄性和雌性大鼠大脑中 [H]-DAMGO 特异性结合 MOR 的水平，而晚期青春期（PN50）和 Pb 暴露雄性大鼠的变化较小（PN120）。具体而言，在 PN14 时，Pb 暴露雄性大鼠的外侧下丘脑后核（LPTN）中的 MOR 结合增加，Pb 暴露雌性大鼠的 LPTN、内侧丘脑和下丘脑中的 MOR 结合增加。在 PN28 时，Pb 暴露雄性大鼠的纹状体、丘脑髓纹、LPTN、内侧丘脑和基底外侧杏仁核中的 MOR 水平增加，而 Pb 暴露雌性大鼠的伏隔核核心、LPTN 和内侧丘脑中的 MOR 水平增加。在雄性和雌性大鼠的任何脑区均未检测到 PN50 时的任何变化，而在 PN120 时，Pb 暴露雄性大鼠的内侧丘脑的 MOR 结合减少。我们的发现表明，慢性发育性 Pb 暴露会导致大鼠大脑中 MOR 水平出现年龄和性别特异性影响。这些结果表明，大脑 MOR 水平的主要变化发生在青春期前和青春期早期，这是人类参与奖励和觅药行为更高的发育时期。总之，我们表明，慢性暴露于 Pb（一种普遍存在且众所周知的环境污染物和神经毒素）会改变青春期大脑中与成瘾回路相关的脑区中的 MOR 水平，这些发现对阿片类药物使用和滥用具有重要意义。
