Dopamine (DA) homeostasis is essential for a variety of brain activities. Dopamine transporter (DAT)-mediated DA reuptake is one of the most critical mechanisms for the control of normal DA homeostasis.

　　In a paper published online by Nature Neuroscience this week, scientists from the Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, identified a new determinant required for the maintenance of DA homeostasis in the mouse brain. They found that a Rho family GEF protein Vav2 is required for glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor Ret-modulated DAT cell surface expression and transporter activity.

　　Co-first authors ZHU Shuyong, ZHAO Chengjiang, WU Yingying, principal investigator ZHOU Jiawei, and colleagues found that that Vav2-deficiency caused DAT hyper-function, which was accompanied with an abnormal increase in intracellular DA levels preferentially in the NAc. Moreover, Vav2 interacted with Ret forming a functional complex and cooperated to robustly down-regulate DAT activity. Their data demonstrate that Vav2 is a determinant of DAT trafficking in vivo and contributes to the maintenance of DA homeostasis in limbic DA neuron terminals. Importantly, Vav2-mediated DAT sequestration machinery functions selectively in a brain region that is critical component of the neural circuitry involved in drug addiction. Vav2^-/- mice exposed to cocaine showed reduced DAT activity and diminished behavioral cocaine response. Together, these results indicate that suppression of Vav2 may be a new approach for combating cocaine addiction.

　　This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the State Key Laboratory of Neuroscience.

　　A proposed model for how Vav2 regulates GDNF/Ret signaling, thereby modulating DAT internalization and DA homeostasis, in the mesolimbic DA neuron terminals of adult mice under physiological conditions.