Role of Rab10 in cocaine-induced behavioral effects is associated with GABAB receptor membrane expression in the nucleus accumbens

Previous studies have demonstrated that Ras-related GTP-binding protein Rab10 (Rab10) plays a role in psychostimulant-induced behavioral effects. In this study, we showed that Rab10 in the nucleus accumbens (NAc) of male animals affects the development of cocaine-induced behavioral effects, which are associated with the plasma membrane expression of the GABA heteroreceptor (GABA R). We performed flow cytometry, immunoendocytosis, pHluorin activity analysis, electrophysiology analysis, and open-field testing to explore the role of Rab10 in modulating the membrane expression and function of GABA R and its regulatory effect on cocaine-induced behavioral effects. Transcriptomics analysis showed that was elevated following acute cocaine treatment. Membrane levels of Rab10 increased within day 1 of the cocaine treatment, subsequently decreasing at later time points. deficiency in NAc regions significantly increased cocaine-inhibited membrane GABA R levels and inhibited cocaine-induced hyperlocomotion and behavioral sensitization. In addition, -expressing neurons from NAc regions treated with cocaine revealed a significant decrease in Rab10 membrane expression. Furthermore, NAc neuron-specific knockout resulted in a significant increase in the cocaine-inhibited membrane expression of GABA R, along with increased miniature inhibitory postsynaptic current (mIPSC) amplitude and attenuation of baclofen-amplified Ca influx. These results uncover a new mechanism in which Rab10-GABA R signaling may serve as a potential pathway for regulating cocaine-induced behavioral effects.