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: 7993054
• 负责人: HELEN J SABLE
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993054
• 关键词: Agonist; Amphetamines; Animal Model; Animals; Behavioral; Brain; Cocaine; Cognitive; Control Animal; Cues; Data; Development; Dopamine; Dopamine Receptor; Dose; Drug Addiction; Drug Controls; Environment; Environmental Pollution; Exposure to; Extinction (Psychology); Goals; Grant; Impairment; Incentives; Individual; Laboratories; Ligands; Medial; Mediating; Mentors; Methods; Performance; Perinatal Exposure; Pharmaceutical Preparations; Phase; Polychlorinated Biphenyls; Predisposition; Prefrontal Cortex; Process; Property; Proteins; Psychostimulant dependence; Rattus; Relative (related person); Research; Risk; Rodent Model; Saline; Stimulus; Substance abuse problem; Toxic effect; Training; Western Blotting; base; behavioral sensitization; cognitive function; dopamine system; inhibitor/antagonist; neurochemistry; phenyl ether; psychostimulant; receptor; receptor expression; response; theories

Relatively little is known about the effects of exposure to environmental contaminants on substance abuse risk. Tiie goal of this project is to determine if developmental exposure to polychlorinated biphenyls (RGBs) 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-associatedUues 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, including inhibitory control. Preliminary results from our laboratory suggest that developmental PCB exposure pre-sensitizes rats to the locomotor activating effects of amphetamine (AMPH), and produces functional tolerance with repeated administration. Based on these findings and previous research examining the effects of PCB exposure on DA function, 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 PCBinduced changes in DA receptor expression in the mPFC mediate both the enhanced psychostimulant sensitivity and the inhibitory control deficits. The specific aims are to: (1) Determine which DA receptor subtypes in the mPFC contribute to enhanced psychostimulant sensitivity in PCB-exposed animals, (2) Determine which DA receptor subtypes in the mPFC are involved in the inhibitory control deficits seen in PCB-exposed animals, and (3) Determine whether developmental exposure to polybrominated diphenyl ethers (PBDEs) results in changes in DA receptor expression and enhanced behavioral sensitization following psychostimulant exposure 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.

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 (RGB) 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症状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，包括抑制控制。我们实验室的初步结果表明，发育过程中的 PCB 暴露会使大鼠对运动激活效应预先敏感 安非他明 (AMPH)，并通过重复给药产生功能耐受性。基于这些发现和先前研究 PCB 暴露对 DA 功能影响的研究，假设早期发育过程中 PCB 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兴奋剂敏感性；（2）确定 PCB 诱导的 mPFC 中 DA 受体表达的变化是否介导增强的精神兴奋剂敏感性和抑制控制缺陷。具体目标是：(1) 确定 mPFC 中的哪些 DA 受体亚型有助于增强 PCB 暴露动物的精神兴奋剂敏感性，(2) 确定 mPFC 中的哪些 DA 受体亚型与 PCB 中出现的抑制控制缺陷有关。 (3) 确定在发育过程中接触多溴二苯醚 (PBDE) 是否会导致 DA 受体表达发生变化，并在接触精神兴奋剂后行为敏感性增强，与PCB 产生的影响。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。