Aquaporin‐4 Deficiency Attenuates Opioid Dependence through Suppressing Glutamate Transporter‐1 Down‐regulation and Maintaining Glutamate Homeostasis

Summary Background 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 ( AQP 4) deficiency attenuated morphine dependence, but the mechanisms are unclear. According to the recent evidence that AQP 4 might form a functional complex with glutamate transporter‐1 ( GLT ‐1), this study focused on whether AQP 4 participates in the modulation of GLT ‐1 and glutamate homeostasis in morphine‐dependent mice. Results We found that AQP 4 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 AQP 4 knockout mice. In addition, AQP 4 knockout abolished both decreases and increases in the extracellular glutamate levels in the prefrontal cortex during repeated morphine treatment and naloxone‐precipitated withdrawal. Conclusion AQP 4 deficiency suppresses the down‐regulation of GLT ‐1, and the disruption of glutamate homeostasis caused by repeated exposure to morphine, pointing to a strategy for maintaining glutamate homeostasis and thereby treating addiction through the modulation of AQP 4 function and expression.