Conditioned place preference to amphetamine following prenatal immune activation

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、消退和恢复背后的学习过程在人类成瘾中起着核心作用。我们对影响药物相关学习和记忆的特定环境因素的了解是不完整的。在其他领域中充分研究的机制是产前感染，其刺激母体细胞因子，介导先天性炎症反应的可溶性多肽。母体细胞因子升高对后代的后果已经在称为“产前免疫激活”的动物模型中使用刺激母体细胞因子表达的合成核酸聚I：C进行了研究。在怀孕期间注射poly I：C改变了对滥用药物作出反应的神经系统后代的功能。来自其他疾病研究的估计表明，多达1/3的药物依赖患者可能在子宫内暴露于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注射对安非他明的条件性位置偏爱的获得、消退和恢复的作用。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谷氨酸和多巴胺在前额叶皮层和核神经元，最终共同途径介导药物复吸的元素传输，从而损害灭绝和促进恢复滥用药物的条件偏好。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后果来检验这一假设。在具体目标2中，我们将确定细胞外谷氨酸和多巴胺在前额叶皮层和神经核预处理，并在药物诱导的恢复产前免疫激活后，使用微透析。在完成这些研究后，我们希望证明产前免疫激活后的行为和神经化学改变与药物复发的风险直接相关。因此，我们预期的研究结果可能表明有机会检测药物复发风险升高的人群，并同时确定在该组中进行干预的新靶点。 公共卫生相关性：我们建议确定产前免疫激活对与药物使用相关的学习和记忆的影响。我们还希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，因为它们将阐明一种常见的环境暴露，产前免疫激活，对药物依赖相关的一个关键结果指标的影响：与药物使用相关的学习和记忆。预期的研究结果可能会促进对药物依赖的预防，治疗和预后的理解。

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.