Aquaporin-4 deficiency attenuates opioid dependence through suppressing glutamate transporter-1 down-regulation and maintaining glutamate homeostasis.
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 (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.


RESULTS
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.


CONCLUSIONS
AQP4 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 AQP4 function and expression.
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Hai-Tao
HT
Yan
Ning
N
Wu
Xin-Qiang
XQ
Lu
Rui-Bin
RB
Su
Jian-Quan
JQ
Zheng
Jin
J
Li
D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D014316:Tritium / Q000378:metabolism
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D018690:Excitatory Amino Acid Agonists; D027342:Excitatory Amino Acid Transporter 2; D009292:Narcotic Antagonists; D014316:Tritium; D009270:Naloxone; D018698:Glutamic Acid; C020889:dihydrokainic acid; D009020:Morphine; D007608:Kainic Acid