Assessment of Psychostimulant Addiction Risk Following Developmental PCB Exposure

发育性 PCB 暴露后精神兴奋剂成瘾风险的评估

• 批准号: 7224533
• 负责人: HELEN J SABLE
• 金额: $ 8.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224533
• 关键词: Adult; Affect; Agonist; Amphetamines; Animal Model; Animals; Area; Behavioral; Brain; Cocaine; Cognitive; Control Animal; Cues; Data; Development; Dopamine; Dopamine Receptor; Dose; Down-Regulation; Drops; Drug Addiction; Drug Controls; Environment; Environmental Pollution; Exposure to; Extinction (Psychology); Female; Flame Retardants; Goals; Impairment; Incentives; Individual; Lactation; Ligands; Martes zibellina; Measures; Medial; Mediating; Mentors; Methods; Motor; Motor Activity; Output; Performance; Perinatal; Pharmaceutical Preparations; Phase; Polychlorinated Biphenyls; Predisposition; Prefrontal Cortex; Pregnancy; Principal Investigator; Process; Property; Proteins; Psychostimulant dependence; Rate; Rattus; Relative (related person); Research; Research Personnel; Risk; Rodent Model; Saline; Schedule; Solid; Stimulus; Substance abuse problem; Testing; Toxic effect; Training; Up-Regulation; Western Blotting; base; behavioral sensitization; cognitive function; dopamine system; dopamine transporter; dopaminergic neuron; drug discrimination; environmental chemical; inhibitor/antagonist; male; neurochemistry; phenyl ether; programs; protein expression; psychostimulant; receptor; receptor expression; research study; response; theories; vesicular monoamine transporter

DESCRIPTION (provided by applicant) Relatively little is known about the effects of exposure to environmental contaminants on substance abuse risk. The goal of this project is to determine if developmental exposure to polychlorinated biphenyls (PCBs) enhances the predisposition to develop drug addiction using a rodent model. Recent theories propose that drug addiction occurs due to increasing incentive salience for the drug and drug-associated cues as well as impaired inhibitory control at the cognitive level. Research in animal models suggests that reduced dopamine (DA) activity in the medial prefrontal cortex (mPFC) may mediate this process. PCB exposure reduces brain DA and impairs mPFC-mediated cognitive functions. Based on these findings it is hypothesized that PCB exposure during early development will result in reduced DA function in mPFC, produce inhibitory control deficits and enhance the incentive salience of psychostimulants. The objectives of the current proposal are to: (1) characterize inhibitory control deficits and determine psychostimulant sensitivity in rats developmentally exposed to an environmentally relevant PCB mixutre and (2) determine whether PCB induced changes in DA receptor expression in the mPFC mediate both the enhanced psychostimulant sensitivity and the inhibitory control deficits. The specific aims of the mentored phase are to: (1) quantify differences in inhibitory control on a multiple fixed interval/extinction task, (2) measure changes in the expression of the dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), D1, D2, and D4 receptor subtypes in the mPFC of rats developmentally exposed to PCBs relative to controls, and (3) determine if perinatal PCB exposure is associated with enhanced sensitivity to the discriminative stimulus or motor-activating properties of psychostimulants. The specific aims of the independent phase are to: (1) determine which DA receptor subtypes in the mPFC mediate the enhanced psychostimulant sensitivity and inhibitory control deficits in PCB-exposed animals, and (2) Determine whether developmental exposure to the polybrominated diphenyl ethers (PBDEs), ubiquitous environmental chemicals which are chemically similar to the PCBs, results in changes in DA receptor expression and enhanced psychostimulant sensitivity that parallel the effects produced by PCBs. The results will provide valuable information about substance abuse risk following developmental exposure to environmental contaminants that target the DA system.

描述（由申请人提供） 关于接触环境污染物对药物滥用风险的影响知之甚少。该项目的目标是利用啮齿动物模型确定发育过程中接触多氯联苯 (PCB) 是否会增强吸毒成瘾的倾向。 最近的理论认为，药物成瘾的发生是由于药物和药物相关线索的激励显着性增加以及认知水平的抑制控制受损所致。 动物模型研究表明，内侧前额皮质 (mPFC) 中多巴胺 (DA) 活性的降低可能会介导这一过程。 PCB 暴露会降低大脑 DA 并损害 mPFC 介导的认知功能。 基于这些发现，推测早期发育过程中 PCB 暴露将导致 mPFC 中 DA 功能降低，产生抑制控制缺陷并增强精神兴奋剂的激励显着性。当前提案的目标是：（1）表征抑制控制缺陷并确定发育中暴露于环境相关 PCB 混合物的大鼠的精神刺激敏感性；（2）确定 PCB 是否诱导 mPFC 中 DA 受体表达的变化介导增强的精神刺激敏感性和抑制控制缺陷。指导阶段的具体目标是：(1) 量化多个固定间隔/消退任务的抑制控制差异，(2) 测量多巴胺转运蛋白 (DAT)、囊泡单胺转运蛋白 (VMAT2) 表达的变化，相对于对照，发育性暴露于 PCB 的大鼠 mPFC 中的 D1、D2 和 D4 受体亚型，以及 (3) 确定围产期 PCB 暴露是否与对 PCB 的敏感性增强相关。精神兴奋剂的辨别刺激或运动激活特性。独立阶段的具体目标是：(1) 确定 mPFC 中的哪些 DA 受体亚型介导 PCB 暴露动物的精神兴奋剂敏感性增强和抑制控制缺陷，以及 (2) 确定多溴二苯醚的发育暴露是否（ PBDEs）是一种普遍存在的环境化学物质，其化学性质与 PCB 相似，会导致 DA 受体表达发生变化，并增强精神兴奋剂敏感性，这与 PCB 产生的作用类似。结果将提供有关发育暴露于针对 DA 系统的环境污染物后的药物滥用风险的宝贵信息。