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: 7743935
• 负责人: HELEN J SABLE
• 金额: $ 22.41万
• 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 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743935
• 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。该项目的目标是确定对多氯联苯（RGB）的发育暴露是否会增强使用啮齿动物模型开发药物成瘾的易感性。最近的理论表明，由于越来越多的药物和药物相关服的激励显着性以及认知水平的抑制性控制受损，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暴露减少了脑DA并损害MPFC介导的认知功能，包括抑制性控制。我们实验室的初步结果表明，发育性PCB暴露预先敏感大鼠运动效应 苯丙胺（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功能的影响的研究，假设PCB在早期发育过程中的暴露将导致MPFC中的DA功能降低，产生抑制性控制缺陷并增强精神刺激剂的激励性显着性。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MPFC中PCB诱导的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控制症状。具体目的是：（1）确定MPFC中的哪些DA受体亚型有助于增强PCB暴露动物的心理刺激性敏感性，（2）确定MPFC中哪些DA受体亚型参与PCB暴露的动物中所见的抑制性对照缺陷，以及（3）确定PROM型脑中的抑制作用（3）是否在多脑元素中（3）确定（3）是否存在（3）精神刺激暴露后，受体表达和增强的行为敏化，与PCB产生的影响相似。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。