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Translin deletion impairs cocaine-induced locomotor sensitization and RGS8 expression in the nucleus accumbens

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Multiple lines of evidence show that the microRNA system plays a prominent role in regulating behavioral responses to psychostimulants. Suppressing microRNA degradation is an effective strategy for elucidating the impact of these intracellular messengers on cellular function. The translin/trax complex is an RNase that appears to mediate degradation of a small number of microRNAs. In this study we investigated the effect of deleting the translin/trax microRNA-degrading enzyme on cocaine-induced behavioral responses in mice. Wild type and Translin (Tsn) KO mice were injected with cocaine and their open-field locomotor activity was monitored. We found that the locomotor activity in response to repeated (5, 10 and 20 mg/kg, i.p.), but not acute (20 mg/kg, i.p.), cocaine exposure was significantly impaired in Tsn KO mice. We identified several microRNAs (412–5p, 412–3p, 93–3p, 7b–3p, and 204–5p) that were significantly increased in the NAc of Tsn KO mice. As regulator of G-protein signaling 8 (RGS8) is a predicted target gene shared by three of these microRNAs, and expressed in the NAc, we confirmed its reduced expression in this region in Tsn KO mice. Moreover, shRNA-mediated knockdown of RGS8 in the NAc attenuated locomotor sensitization to repeated cocaine administration. Taken together, our results suggest that microRNAs targeted by the translin/trax RNase inhibit cocaine-induced locomotor sensitization, in part, by silencing expression of RGS8.

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Fig. 1: Tsn KO mice display normal levels of cocaine, cocaine-induced locomotor activity, and dopamine metabolites in brain.
Fig. 2: Tsn KO mice display decreased locomotor activity in response to repeated administration of cocaine, but normal CPP.
Fig. 3: Translin/trax and Dicer1 expression after cocaine exposure.
Fig. 4: Comparison of microRNA expression pattern in NAc in Tsn KO and WT mice.
Fig. 5: RGS8 targeted by several microRNAs is decreased in NAc of Tsn KO mice.
Fig. 6: Working model of cocaine-induced locomotor sensitization regulation by the translin/trax (TN/TX) complex and RGS8.

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Acknowledgements

This study was supported by extramural funds from NIDA, the Mid-Atlantic Nutrition Obesity Research Center. Working model created with Generic Diagramming Platform (https://biogdp.com/).

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Authors and Affiliations

  1. School of Life Sciences, Tiangong University, Tianjin, 300387, China

    Xiu-ping Fu & Ren-kun Wu

  2. Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Xiu-ping Fu, Aparna P. Shah & Jay M. Baraban

  3. Molecular Neuropsychiatry Research Branch, Intramural Research Program, NIDA/NIH/DHHS, Baltimore, MD, 21224, USA

    Bruce Ladenheim & Jean Lud Cadet

  4. John Hopkins Drug Discovery, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Jesse Alt & Rana Rais

  5. Department of Neurobiology, University of Maryland School of Medicine Baltimore, Baltimore, MD, 21201, USA

    Ramesh Chandra

  6. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China

    Xiao-bo Cen

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Contributions

XPF contributed to the design of experiments, the acquisition, analysis, and interpretation of the data, and the writing of the manuscript. RKW, APS, BL, JA, RC, JLC, RR, XBC contributed to data acquisition and analysis, revision of the manuscript. JMB was responsible for overseeing all parts of the study and directly contributed to the interpretation of the results and writing of the paper. All co-authors provided final approval of the manuscript to be published.

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Correspondence to Xiu-ping Fu or Jay M. Baraban.

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Fu, Xp., Wu, Rk., Shah, A.P. et al. Translin deletion impairs cocaine-induced locomotor sensitization and RGS8 expression in the nucleus accumbens. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01565-z

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