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