Mouse Model of OPRM1 (A118G) Polymorphism Increases Sociability and Dominance and Confers Resilience to Social Defeat
Mouse Model of OPRM1 (A118G) Polymorphism Increases Sociability and Dominance and Confers Resilience to Social Defeat
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DOI：
10.1523/jneurosci.4685-14.2015
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发表时间：
2015-02-25
影响因子：
5.3
通讯作者：
Berton, Olivier
中科院分区：
文献类型：
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作者：
Briand, Lisa A.;Hilario, Monica;Berton, Olivier
人类μ阿片受体基因（OPRM 1 A118 G）的单核苷酸多态性（SNP）已被广泛研究，其与药物成瘾，疼痛敏感性以及最近的社会行为的关联。内源性阿片系统已被证明在各种动物模型中调节社会痛苦和奖励。然而，OPRM 1 A118 G SNP与这些行为之间的关联机制尚未阐明。我们使用了一个小鼠模型，具有人类等效的核苷酸/氨基酸取代，研究社会联系和社会失败行为。在Oprm 1 A112 G SNP小鼠中，我们证明了G等位基因与家庭笼优势的增加和非攻击性社会互动的动机增加相关，与人类群体中报道的相似。当受到常驻攻击者的挑战时，G等位基因携带者表现出较少的顺从行为，并表现出对社会失败的恢复力，表现为缺乏随后的社交回避和减少快感缺乏，如颅内自我刺激所测量的。在G等位基因携带者中，防止社交失败与由中脑核和导水管周围灰质组成的弹性回路中c-fos的更大诱导相关。这些发现使我们测试内源性阿片类物质在A112 G小鼠中的作用。我们证明，纳洛酮预处理阻断了携带者社会联系的增加。总之，这些数据表明一种机制，涉及改变享乐状态和神经激活，以及改变内源性阿片类药物的音调在G等位基因携带者的厌恶和奖励的社会刺激的差异反应。
A single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in drug addiction, pain sensitivity, and, more recently, social behavior. The endogenous opioid system has been shown to regulate social distress and reward in a variety of animal models. However, mechanisms underlying the associations between the OPRM1 A118G SNP and these behaviors have not been clarified. We used a mouse model possessing the human equivalent nucleotide/ amino acid substitution to study social affiliation and social defeat behaviors. In mice with the Oprm1 A112G SNP, we demonstrate that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions, similar to what is reported in human populations. When challenged by a resident aggressor, G-allele carriers expressed less submissive behavior and exhibited resilience to social defeat, demonstrated by a lack of subsequent social avoidance and reductions in anhedonia as measured by intracranial self-stimulation. Protection from social defeat in G-allele carriers was associated with a greater induction of c-fos in a resilience circuit comprising the nucleus accumbens and periaqueductal gray. These findings led us to test the role of endogenous opioids in the A112G mice. Wedemonstrate that the increase in social affiliation inGcarriers is blocked by pretreatment with naloxone. Together, these data suggest a mechanism involving altered hedonic state and neural activation as well as altered endogenous opioid tone in the differential response to aversive and rewarding social stimuli in G-allele carriers.