Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects
Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects
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DOI：
10.1371/journal.pone.0001640
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发表时间：
2008-02-20
期刊：
影响因子：
3.7
通讯作者：
Uhl, George R.
中科院分区：
文献类型：
--
作者：
Onaivi, Emmanuel S.;Ishiguro, Hiroki;Uhl, George R.
背景资料：成瘾和重性抑郁症是与生活中的压力事件相关的心理健康问题，即使在治疗后也有很高的复发率和复发率。许多实验室无法检测健康大脑中大麻素CB 2受体（CB 2-Rs）的存在，但在炎症过程中，大鼠小胶质细胞和其他脑相关细胞中的CB 2-R表达已得到证实。因此，CB 2-Rs的神经元表达一直是模棱两可的和有争议的，它在抑郁症和药物滥用的作用是unknow.Methodology/主要发现：在这项研究中，我们测试的假设，CB 2基因的遗传变异可能与抑郁症在人群中，CB 2基因表达的改变可能参与滥用物质，包括阿片类药物，可卡因和乙醇在啮齿动物的影响。在这里，我们证明了高发病率（Q63 R），但没有（H316 Y）多态性的CB 2基因被发现在日本抑郁症的主题。CB 2-Rs及其基因转录物在幼稚小鼠的大脑中表达，并在暴露于应激源和滥用药物后受到调节。酒精偏好的小鼠降低了CB 2基因表达，并且用JWH 015（一种假定的CB 2-R激动剂）长期治疗，增加了应激小鼠的酒精消耗，但在对照小鼠中没有。将CB 2反义寡核苷酸直接脑室内显微注射到小鼠脑中减少了小鼠在十字迷宫测试中的厌恶，表明CB 2-Rs在脑中的功能存在改变了行为。我们报告使用电子显微镜的亚细胞定位的CB 2-Rs，主要是对突触后元件在啮齿动物brain.Conclusions/Significance：我们的数据表明CB 2-Rs在大脑中的功能表达，可能提供新的目标大麻素的影响，在抑郁症和物质滥用障碍超出神经免疫annabinoid活性。
Background: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown.Methodology/Principal Findings: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naive mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain.Conclusions/Significance: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.