Neuronal cell adhesion molecule regulating neural systems underlying addiction
Neuronal cell adhesion molecule regulating neural systems underlying addiction
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DOI：
10.1002/npr2.12038
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发表时间：
2019-03-01
影响因子：
2.5
通讯作者：
Onaivi, Emmanuel S.
中科院分区：
文献类型：
--
作者：
Ishiguro, Hiroki;Miyake, Kunio;Onaivi, Emmanuel S.
目的：人类NRCAM基因与多物质使用有关。Nrcam基因敲除小鼠不会获得对成瘾物质的偏好。我们的目的是阐明Nrcam在先天性物质偏好和成瘾习得的特定神经回路中的作用。方法：分析神经分子的基因表达模式，寻找依赖Nrcam功能的常见成瘾通路。我们使用微阵列基因表达分析方法检测了在冰毒（METH）或生理盐水（SAL）治疗后Nrcam基因敲除小鼠大脑中的单胺能、谷氨酸能和gaba能系统，并使用TaqMan基因表达分析方法进行了复制。为了找到一个共同的成瘾途径，我们研究了men处理小鼠和可卡因（COC）处理Nrcam敲除小鼠分子表达模式的异同。结果：甲基安非他明和COC处理后Nrcam杂合小鼠脑内谷氨酰胺酶表达降低，与我们前期研究一致。在接受甲基安非他明或COC治疗的Nrcam杂合小鼠中，代谢性谷氨酸受体2的表达降低。其他一些分子可能在包括冰毒或COC在内的独立成瘾途径中起作用。我们还发现，在接受SAL治疗的Nrcam杂合小鼠中，GABA受体亚单位g2的表达减少，而甲基安非他明治疗则减弱了这种减少。结论：Nrcam对幼龄和获得性成瘾动物脑内谷氨酸能和gaba能分子的调节存在差异。阐明多物质使用背后的复杂神经机制将揭示成瘾的生物学特征，并可能有助于开发有效的药物治疗。
Aims: The human NRCAM gene is associated with polysubstance use. Nrcam knockout mice do not acquire a preference for addictive substances. We aimed to elucidate the role of Nrcam in specific neural circuits underlying congenital preference for substances and the acquisition of addiction.Methods: We analyzed gene expression patterns of neural molecules to find a common addiction pathway dependent on Nrcam function. We examined monoaminergic, glutamatergic, and GABAergic systems in the brains of Nrcam knockout mice following treatment with methamphetamine (METH) or saline (SAL) using micro-array gene expression analysis, which was replicated using TaqMan gene expression analysis. To find a common addiction pathway, we examined similarities and differences between the expression patterns of molecules in MEN-treated mice and in Nrcam knockout mice treated with cocaine (COC).Results: Glutaminase expression in brain was reduced in Nrcam heterozygous mice after METH and COC treatment, consistent with our previous study. Metabotropic glutamate receptor 2 expression was reduced in Nrcam heterozygous mice that received either METH or COC treatment. Several other molecules could act in independent addiction pathways involving METH or COC. We also found that GABA receptor subunit g2 expression was reduced in Nrcam heterozygous mice that underwent SAL treatment, and that METH treatment attenuated this reduction.Conclusion: Nrcam differentially regulates glutamatergic and GABAergic molecules in naive brains and in brains of animals with acquired addiction. Elucidating the complex neural mechanisms underlying polysubstance use will uncover biological features of addiction and may contribute to the development of effective pharmaceutical treatments.