Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

现有研究表明，娱乐性药物（recreational drugs）、酒精与3,4-亚甲二氧基甲基苯丙胺（3,4-Methylenedioxymethamphetamine, MDMA，俗称“摇头丸”）均可在体内（in vivo）引发免疫激活，且在啮齿类动物（rodents）中与认知损伤（cognitive impairment）及焦虑样行为（anxiety-like behaviors）存在关联。此类药物在海马区（hippocampal area）的神经效应仍有待阐明；而海马区作为阐释焦虑相关障碍（anxiety-related disorders）潜在机制的研究热点区域，其相关药物作用的神经机制目前尚不清楚。因此本研究旨在探究酒精与MDMA对该脑区以及海马相关行为任务的特异性炎症影响。本研究聚焦于两种与焦虑相关障碍密切相关的炎症因子：白细胞介素-1β（Interleukin-1β, IL-1β）与脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）。我们让摄入药物的小鼠接受一系列行为学实验（battery of behavioral tests），以评估其整体活动水平、焦虑样与抑郁样行为（depressive-like behaviors）；随后对小鼠实施情境恐惧辨别任务（contextual fear discrimination task），并通过免疫组织化学（immunohistochemical）与生物化学（biochemical）实验检测相关免疫效应。研究结果显示，自愿饮酒（voluntary alcohol consumption）与高剂量MDMA（high-dose MDMA）均可诱导免疫激活通路（immune activated pathways），二者存在相关性。此外，药物暴露会损伤小鼠完成情境恐惧辨别任务的能力；本研究还发现，即使在药物摄入数周后，小鼠海马区仍存在长期炎症改变。本研究结果可为焦虑相关障碍患者的新型选择性药物靶点发掘、治疗方案与预防策略开发提供有益参考。