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） 关于暴露于环境污染物对药物滥用风险的影响相对鲜为人知。该项目的目的是确定使用啮齿动物模型增强了对多氯联苯（PCB）的发育暴露是否会增强产生药物成瘾的倾向。 最近的理论表明，由于增加了药物和药物相关线索的激励性显着性以及认知水平上的抑制性控制受损，因此吸毒成瘾发生。 动物模型的研究表明，内侧前额叶皮层（MPFC）中多巴胺（DA）活性降低可能介导此过程。 PCB暴露会减少脑DA并损害MPFC介导的认知功能。 根据这些发现，假设PCB在早期发育过程中的暴露将导致MPFC的DA功能降低，产生抑制性控制缺陷并增强精神刺激物的激励显着性。当前建议的目标是：（1）表征抑制性控制缺陷，并确定在发育中暴露于环境相关的PCB混合物的大鼠中的精神刺激性敏感性，并且（2）确定PCB诱导的MPFC中DA受体表达的变化是否介导了增强的心理刺激性敏感性和抑制性对照。指导阶段的具体目的是：（1）量化对多个固定间隔/灭绝任务的抑制性控制差异，（2）测量多巴胺转运蛋白转运蛋白（DAT），囊泡单胺转运蛋白转运蛋白（VMAT2），D1，D2和D4受体子类型的变化的变化。围产期PCB暴露与对歧视性刺激或心理刺激物的运动激活特性的敏感性增强有关。 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 PCBS产生的效果平行的精神刺激敏感性。结果将提供有关滥用药物滥用风险的有价值的信息，因为发育范围暴露于针对DA系统的环境污染物。