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，因为与药物相关的联系的获得、消失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是不完整的。在其他领域研究得很好的一个机制是产前感染，它刺激母体细胞因子，可溶性多肽介导先天炎症反应。在一种名为“产前免疫激活”的动物模型中，研究了母体细胞因子升高对后代的影响，该动物模型使用合成核酸Poly I：C刺激母体细胞因子的表达。怀孕期间注射Poly I：C会改变参与药物滥用反应的神经系统的后代的功能。对其他疾病研究的估计表明，多达三分之一的药物依赖患者可能在宫内暴露于刺激母体细胞因子表达的条件下。本应用的目的是表征聚I：C注射对苯丙胺的条件性位置偏爱的获得、消退和恢复的影响。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叶皮质和伏隔核中的谷氨酸和多巴胺的传递，这是最终共同途径中介导药物复发的元素，从而损害了药物的消亡，并促进了对滥用药物的条件性偏好的恢复。我们将在特定的目标1中测试这一假设，方法是确定产前免疫激活对获得、消亡以及药物和压力诱导的条件位置偏爱恢复安非他明的后果。在特定的目标2中，我们将用微透析法测定条件作用前的前额叶皮质和伏隔核中的细胞外谷氨酸和多巴胺，以及在产前免疫激活后药物诱导的恢复过程中。在这些研究完成后，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，我们的预期发现可能会为发现药物复发风险较高的人群提供机会，并同时确定对这一群体进行干预的新靶点。

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.