['Glutamate homeostasis plays a critical role in mediating the addiction-related behaviors. Therefore, preventing the disruption or reestablishing of it is a novel strategy for the treatment of addiction. Glutamate transporters are responsible for clearing extracellular glutamate and maintaining glutamate homeostasis. Our previous work demonstrated that aquaporin-4 (AQP4) deficiency attenuated morphine dependence, but the mechanisms are unclear. According to the recent evidence that AQP4 might form a functional complex with glutamate transporter-1 (GLT-1), this study focused on whether AQP4 participates in the modulation of GLT-1 and glutamate homeostasis in morphine-dependent mice.', 'We found that AQP4 knockout prevented the down-regulations of GLT-1 expression and glutamate clearance when mice were repeatedly treated with morphine. Further study revealed that inhibition of GLT-1 by dihydrokainic acid (DHK) initiated morphine dependence in AQP4 knockout mice. In addition, AQP4 knockout abolished both decreases and increases in the extracellular glutamate levels in the prefrontal cortex during repeated morphine treatment and naloxone-precipitated withdrawal.'] Does aquaporin-4 deficiency attenuate opioid dependence through suppressing glutamate transporter-1 down-regulation and maintaining glutamate homeostasis?