Albores-Garcia Damaris, Stansfield Kirstie H, McGlothan Jennifer L, Bursac Zoran, Guilarte Tomás R
Brain, Behavior and the Environment Laboratory, Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, United States.
InVitro Cell Research, LLC, New York, NY, United States.
Front Mol Neurosci. 2022 Aug 24;15:946726. doi: 10.3389/fnmol.2022.946726. eCollection 2022.
Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb) intoxication and schizophrenia (SZ). In animal models, Pb exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb exposure affects addiction circuits, we hypothesized that early life Pb exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb exposure increases the acute locomotor response to the higher dose of cocaine in Pb-exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb-exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb-induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb exposure. Our data provides further support to the notion that Pb exposure is an environmental risk factor for psychiatric disorders and substance abuse.
接触重金属与精神疾病有关，最近的研究表明儿童期铅（Pb）中毒与精神分裂症（SZ）之间存在关联。在动物模型中，铅暴露重现了精神分裂症中存在的关键神经病理学和多巴胺能系统改变。鉴于精神分裂症和药物滥用等精神障碍的高共病性，再加上有证据表明铅暴露会影响成瘾回路，我们推测早年铅暴露可能会使与精神分裂症和药物滥用相关的神经元系统敏感化。为了实现这一目标，我们研究了慢性发育性铅暴露对可卡因（0、5和15毫克/千克）急性运动反应和行为敏化的影响。我们还研究了多巴胺能系统在可卡因精神兴奋作用中的作用，并使用[H]-SCH23390定量受体放射自显影术测量大鼠脑中D1-多巴胺受体（D1R）水平，以及D1R拮抗剂SCH23390阻断可卡因对运动激活作用的能力。这些研究在不同发育年龄的雄性和雌性大鼠中进行，包括幼年（出生后，PN14）、青少年早期（PN28）、青少年晚期（PN50）和成年（PN120）。我们的结果表明，慢性发育性铅暴露会增加铅暴露雄性青少年（PN28和PN50）大鼠对高剂量可卡因的急性运动反应，以及青少年雌性大鼠对低剂量可卡因的急性运动反应。成年大鼠未检测到运动活动的变化。行为敏化实验表明，青少年早期铅暴露的雄性大鼠而非雌性大鼠存在持续的敏化现象。注射D1R拮抗剂可消除可卡因对运动活动的影响，表明该多巴胺受体亚型参与其中。此外，铅诱导的几个脑区D1R水平升高在幼年和青少年早期较为显著，但在青少年晚期或成年期则不明显。总之，早年慢性发育性铅暴露对可卡因的运动反应产生年龄和性别依赖性影响，表明对铅暴露神经毒性作用的易感性存在差异。我们的数据进一步支持了铅暴露是精神疾病和药物滥用的环境风险因素这一观点。
