Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
Sci Rep. 2021 Jan 28;11(1):2567. doi: 10.1038/s41598-021-82206-3.
To identify signaling pathways activated by oxycodone self-administration (SA), Sprague-Dawley rats self-administered oxycodone for 20 days using short-(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized 2 h after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs, in the LgA-H rats. GluA3, but not GluA2, mRNA expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. These findings suggest that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation and increases in striatal gene expression. These observations offer potential avenues for interventions against oxycodone addiction.
为了确定阿片类药物自我给药（SA）激活的信号通路，斯普拉格-道利大鼠使用短（ShA，3 小时）和长（LgA，9 小时）给药范式进行了 20 天的阿片类药物自我给药。在 SA 停止后 2 小时处死动物，并在后脑纹状体进行死后分子分析。LgA 大鼠增加了阿片类药物的摄入量，并分为低（LgA-L）或高（LgA-H）阿片类药物摄取者。LgA-H 大鼠表现出纹状体 ERK1/2 和 MSK1/2 蛋白磷酸化增加。组蛋白 H3，丝氨酸 10 磷酸化和赖氨酸 14 乙酰化（H3S10pK14Ac），MSK1/2 的靶标，仅在 LgA-H 大鼠中显示出增加的丰度。RT-qPCR 分析显示 LgA-H 大鼠 AMPA 受体亚基 GluA2 和 GluA3 mRNA 增加。GluA3，但不是 GluA2，mRNA 表达与 pMSK1/2 和 H3S10pK14Ac 的变化呈正相关。这些发现表明，阿片类药物自我给药的增加导致 MSK1/2 依赖性组蛋白磷酸化和纹状体基因表达增加。这些观察结果为对抗阿片类药物成瘾提供了潜在的干预途径。
