Conditioned place preference to amphetamine following prenatal immune activation

产前免疫激活后对安非他明的条件性位置偏好

基本信息

批准号：
8302069
负责人：
NEIL MARK RICHTAND
金额：
$ 23.55万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302069
关键词：
Address Amphetamines Animal Model Behavior Behavioral Development Disease Dopamine Dose Drug Addiction Drug usage Elements Environment Environmental Risk Factor Exposure to Extinction (Psychology)Glutamates Goals Human Immune Infection Inflammatory Inflammatory Response Injection of therapeutic agent Intervention Knowledge Learning Link Measures Mediating Memory Microdialysis Modality Modeling Neurons Nucleus Accumbens Outcome Outcome Measure Pathway interactions Patients Perinatal Exposure Pharmaceutical Preparations Play Poly I-C Population Prefrontal Cortex Pregnancy Prevention Process Rewards Risk Risk Factors Role Schedule Stress System Testing Training Translating Translations addiction clinical practice conditioned fear conditioning cytokine drug of abuse drug relapse effective therapy extracellular immune activation indexing innovation maternal stress neurochemistry novel offspring outcome forecast polypeptide pre-clinical preference prenatal prenatal environmental exposure prenatal stress response synthetic nucleic acid transmission process

项目摘要

DESCRIPTION (provided by applicant): Addiction has been described as a disease of learning and memory, as the learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play a central role in human addictions. Our knowledge of specific environmental factors influencing drug-associated learning and memory is incomplete. A well-studied mechanism in other fields is prenatal infection, which stimulates maternal cytokines, soluble polypeptides mediating the innate inflammatory response. Consequences to the offspring of maternal cytokine elevation have been studied in an animal model termed "prenatal immune activation" using the synthetic nucleic acid poly I:C, which stimulates maternal cytokine expression. Injecting poly I:C during pregnancy alters function in the offspring of neuronal systems involved in response to drugs of abuse. Estimates from studies of other disorders suggest as many as 1/3 of drug dependent patients may have had in utero exposure to conditions stimulating maternal cytokine expression. The objective of this application is to characterize the effect of poly I:C injection on acquisition, extinction, and reinstatement of conditioned place preference to amphetamine. We will also identify neurochemical indices of relevance to these behaviors. Our overarching hypothesis is that prenatal immune activation alters glutamate and dopamine transmission in prefrontal cortex and nucleus accumbens, elements of the final common pathway mediating drug relapse, thereby impairing extinction and facilitating reinstatement of conditioned preference for drugs of abuse. We will test this hypothesis in Specific Aim 1 by determining the consequence of prenatal immune activation on acquisition, extinction, and drug- and stress-induced reinstatement of conditioned place preference to amphetamine. In Specific Aim 2, we will determine extracellular glutamate and dopamine in prefrontal cortex and nucleus accumbens preceding conditioning, and during drug-induced reinstatement following prenatal immune activation using microdialysis. Upon completion of these studies, we expect to demonstrate behavioral and neurochemical alterations following prenatal immune activation of direct relevance to the risk for drug relapse. Our expected findings may therefore suggest opportunities to detect a population at elevated risk for drug relapse, and simultaneously identify novel targets for intervention in this group. PUBLIC HEALTH RELEVANCE: We propose to determine the effect of prenatal immune activation on learning and memory associated with drug use. We also expect to identify neurochemical mechanisms contributing to the observed behavioral effects. Our expected outcomes are important because they will elucidate the effect of a common environmental exposure, prenatal immune activation, on a key outcome measure of relevance to drug dependence: learning and memory associated with drug use. The expected findings may advance the understanding of prevention, treatment, and prognosis for drug dependence.

描述（由申请人提供）：成瘾被描述为一种学习和记忆疾病，因为药物配对关联的获得、消除和恢复的学习过程在人类成瘾中发挥着核心作用。我们对影响药物相关学习和记忆的特定环境因素的了解并不完整。其他领域经过充分研究的机制是产前感染，它会刺激母体细胞因子，即介导先天炎症反应的可溶性多肽。母体细胞因子升高对后代的影响已经在称为“产前免疫激活”的动物模型中进行了研究，该模型使用合成核酸聚 I:C，刺激母体细胞因子的表达。怀孕期间注射 Poly I:C 会改变后代对滥用药物做出反应的神经元系统的功能。对其他疾病的研究估计表明，多达 1/3 的药物依赖患者可能在子宫内曾接触过刺激母体细胞因子表达的条件。本申请的目的是表征聚 I:C 注射对安非他明条件性位置偏好的获得、消除和恢复的影响。我们还将确定与这些行为相关的神经化学指标。我们的总体假设是，产前免疫激活改变了前额皮质和伏核中谷氨酸和多巴胺的传递，这是介导药物复发的最终共同途径的要素，从而损害了灭绝并促进了对滥用药物的条件性偏好的恢复。我们将在具体目标 1 中通过确定产前免疫激活对安非他明条件性位置偏好的获得、消退以及药物和压力诱导的恢复的影响来检验这一假设。在具体目标 2 中，我们将使用微透析测定预处理前的前额皮质和伏核中的细胞外谷氨酸和多巴胺，以及产前免疫激活后药物诱导的恢复过程中的细胞外谷氨酸和多巴胺。完成这些研究后，我们希望证明产前免疫激活后的行为和神经化学变化与药物复发的风险直接相关。因此，我们预期的结果可能表明有机会检测药物复发风险较高的人群，并同时确定该人群的新干预目标。公共卫生相关性：我们建议确定产前免疫激活对与吸毒相关的学习和记忆的影响。我们还期望确定有助于观察到的行为效应的神经化学机制。我们的预期结果很重要，因为它们将阐明常见环境暴露、产前免疫激活对与药物依赖相关的关键结果指标的影响：与药物使用相关的学习和记忆。预期的发现可能会增进对药物依赖的预防、治疗和预后的理解。