Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice
Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice
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DOI：
10.1016/j.neures.2019.02.007
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发表时间：
2020-02-01
影响因子：
2.9
通讯作者：
Nishi, Akinori
中科院分区：
文献类型：
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作者：
Hikida, Takatoshi;Morita, Makiko;Nishi, Akinori
药物成瘾行为的发展受遗传和环境危险因素的调节。然而，分子机制尚不清楚。为了解决青少年压力在药物成瘾发展中的作用，我们结合了一个转基因小鼠模型，其中在朊蛋白启动子表达控制下的推定显性阴性DISCI形式被用作遗传风险因素，青少年社会隔离压力作为基因-环境相互作用（GXE）。与其他组相比，GXE组的重复可卡因暴露诱导了更大的运动。在条件位置偏好（CPP）测试中，GXE小鼠与其他组相比，对可卡因条件区域表现出显著的位置偏好。在GXE小鼠伏隔核（NAc）中，我们发现磷酸二酯酶4 （PDE4）酶活性增加，主要位于NAc d2受体表达神经元中，PDE4抑制剂罗利普兰（rolipram）对PKA位点DARPP-32和G1uAI磷酸化的作用增强，而D1激动剂SKF81297则没有作用。在可卡因暴露前注射罗利普兰完全抑制GXE组可卡因诱导的过度运动和CPP。这些结果表明，GXE通过增加NAc d2受体表达神经元中PDE4的活性来增强对重复可卡因暴露的敏感性，从而导致可卡因成瘾行为的发展。(C) 2019 Elsevier B.V.和日本神经科学学会。版权所有。
Development of drug addictive behaviors is modulated by both genetic and environmental risk factors. However, the molecular mechanisms remain unknown. To address the role of adolescent stress in the development of drug addiction, we combined a transgenic mouse model in which a putative dominant-negative form of DISCI under expressional control of the prion protein promoter is used as a genetic risk factor and adolescent social isolation stress as a gene-environmental interaction (GXE). Repeated cocaine exposure induced greater locomotion in the GXE group than in the other groups. In a conditioned place preference (CPP) test, GXE mice exhibited a significant place preference to the cocaine-conditioned area compared with the other groups. In the nucleus accumbens (NAc) of GXE mice, we found increased enzyme activity of phosphodiesterase-4 (PDE4), predominantly located in NAc D2-receptor-expressing neurons, and enhanced effects of the PDE4 inhibitor rolipram, but not the D1 agonist SKF81297, on the phosphorylation of DARPP-32 and G1uAI at PKA sites. Rolipram injection before cocaine exposure completely inhibited cocaine-induced hyperlocomotion and CPP in the GXE group. These results indicate that GXE enhances sensitivity to repeated cocaine exposure via an increase in PDE4 activity in NAc D2-recptor-expressing neurons, leading to the development of cocaine addictive behaviors. (C) 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.