Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine, Ningbo University, 42th Xibei Str, Ningbo, 315010, People's Republic of China.
Metab Brain Dis. 2019 Aug;34(4):1029-1041. doi: 10.1007/s11011-019-00430-3. Epub 2019 Jun 1.
Increasing evidence indicates that excessive drug consumption is sufficient for the transition from recreational and controlled drug use to uncontrolled use and addiction. However, the underlying mechanisms are debated. Some neurobehavioral and neuroimaging evidence indicates that dorsolateral striatum (dlStr)-dependent habit learning plays a key role in excessive drug intake and the transition to addiction, but little is known about the molecular events. The present study investigated whether dlStr miR-134, an important regulator of synaptic transmission and plasticity, is involved in excessive methamphetamine intake. We established excessive and uncontrolled methamphetamine self-administration model in rats by permitting animals extended access to drug (6 h/session/d, LgA group), whereas animals that were limited to access to drug (2 h/session/d, ShA group) exhibited low and controlled self-administration. miR-134 expression in dlStr was significantly increased and its target LIMK1 expression was decreased in the LgA group, but not in the ShA group, compared with the saline control group. However, passive methamphetamine exposure did not alter miR-134 and LIMK1 levels in dlStr. We also found that down-regulation of miR-134 in dlStr through local microinjection of a lentivirus carrying miR-134 sponge (LV-miR-134-Sil) significantly reduced methamphetamine infusions and excessive consumption in LgA group, rather than ShA group. These results indicated that dlStr miR-134, perhaps via its target LIMK1, contributed to excessive and uncontrolled methamphetamine intake, supporting the hypothesis that stimulus-response habit formation is an important mechanism underlying the transition from controlled drug use to uncontrolled drug use and addiction.
越来越多的证据表明，过度药物消耗足以使人们从娱乐性和控制性药物使用过渡到非控制性使用和成瘾。然而，其潜在的机制仍存在争议。一些神经行为学和神经影像学的证据表明，背外侧纹状体（dlStr）依赖的习惯学习在过度药物摄入和成瘾过渡中起着关键作用，但对于其分子事件知之甚少。本研究旨在探讨 dlStr 中的 microRNA-134（miR-134）是否参与了过度甲基苯丙胺摄入。我们通过允许动物延长接触药物的时间（6 小时/次/天，LgA 组）建立了过度和非控制性甲基苯丙胺自我给药模型，而限制动物接触药物（2 小时/次/天，ShA 组）的动物表现出低且控制性的自我给药。与生理盐水对照组相比，LgA 组 dlStr 中的 miR-134 表达显著增加，其靶基因 LIMK1 的表达减少，但 ShA 组没有这种变化。然而，被动给予甲基苯丙胺并没有改变 dlStr 中的 miR-134 和 LIMK1 水平。我们还发现，通过局部注射携带 miR-134 海绵的慢病毒（LV-miR-134-Sil）下调 dlStr 中的 miR-134，可显著减少 LgA 组而非 ShA 组的甲基苯丙胺注射量和过度消耗量。这些结果表明，dlStr 中的 miR-134 可能通过其靶基因 LIMK1 导致过度和非控制性甲基苯丙胺摄入，支持了这样一种假设，即刺激-反应习惯形成是从控制性药物使用过渡到非控制性药物使用和成瘾的重要机制。
