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Dorsolateral striatal miR-134 modulates excessive methamphetamine intake in self-administering rats

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Abstract

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.

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Acknowledgments

This work was supported by the National Key R&D Program of China (2017YFC1310404), National Natural Science Foundation of China (Nos. U1502225 and 81571302) and the National Basic Research Program of China (2015CB553504).

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Authors and Affiliations

  1. 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

    Jing-Jing Shi, Dan-Ni Cao, Zhi-Yuan Wang, Guan-Yi Lu, Ning Wu & Jin Li

  2. 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

    Hui-Fen Liu & Wen-Hua Zhou

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  1. Jing-Jing Shi
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Shi, JJ., Cao, DN., Liu, HF. et al. Dorsolateral striatal miR-134 modulates excessive methamphetamine intake in self-administering rats. Metab Brain Dis 34, 1029–1041 (2019). https://doi.org/10.1007/s11011-019-00430-3

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