Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety
Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety
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DOI：
10.1038/s41386-018-0305-4
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发表时间：
2019-07-01
影响因子：
7.6
通讯作者：
Self, David W.
中科院分区：
文献类型：
--
作者：
Anderson, Ethan M.;Sun, Haosheng;Self, David W.
共病的神经精神障碍，如成瘾和焦虑可能涉及共同的潜在机制。一个潜在的机制涉及组蛋白二甲基转移酶G9 a对组蛋白3在赖氨酸9残基（H3 K9 me 2）处的二甲基化的表观遗传调节。在这里，我们提供的证据表明，局部AAV-RNAi介导的敲低G9 a表达的核壳（NAcSh）的雄性大鼠减少成瘾相关和焦虑相关的行为。具体地，当可卡因是自由可得的（固定比率方案）时，G9 a敲低降低对低剂量可卡因强化的敏感性。类似地，G9 a敲低降低了在更高努力要求下对可卡因的动机（渐进比率计划）。在几周的强制禁欲后，G9 a敲低减弱了由可卡因引发注射或足电击应激引发的消退反应和恢复。这种成瘾行为的减少与高架十字迷宫（elevated plus maze，简称EFL）测量的焦虑样行为的长期减少有关。G9 a基因敲除还减少了未用药大鼠在睡眠和大理石掩埋测试中的基础焦虑样行为。这些结果补充了我们先前的工作，表明NAcSh中G9 a表达的增加增强了成瘾相关和焦虑相关的行为，表明G9 a双向控制这些反应。这些结果还表明，G9 a影响的基因表达的调节可能是共病焦虑和精神兴奋剂成瘾的常见表观遗传机制。
Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule). Similarly, G9a knockdown reduces motivation for cocaine under higher effort demands (progressive ratio schedule). Following several weeks of forced abstinence, G9a knockdown attenuates extinction responding and reinstatement triggered by either cocaine-priming injections or footshock stress. This decrease in addictive behavior is associated with a long-term reduction in anxiety-like behavior as measured by the elevated plus maze (EPM). G9a knockdown also reduces basal anxiety-like behavior in EPM and marble burying tests in drug-naive rats. These results complement our previous work showing that increased G9a expression in NAcSh enhances addictive-related and anxiety-related behaviors, indicating that G9a bi-directionally controls these responses. These results also suggest that regulation of G9a-influenced gene expression could be a common epigenetic mechanism for co-morbid anxiety and psychostimulant addiction.