Aquaporin4 Gene Knock On Morphine-induced Conditioned Place Preference, And The Inhibition Of Nerve Regeneration

In the central nervous system, aquaporin-4 (AQP4) is the most abundant isoform of water transporting channels and is localized in ependymal cells lining the ventricles and astrocyte membranes . AQP4 has gained much attraction due to its involvement in the regulation of the considerable physiologic function, including maintenance of the microenvironment, neuro-transmission, neurogenesis, and so on. Our previous study has shown that AQP4 deficiency could potentiate morphine analgesia, attenuate morphine tolerance and physical dependence. However, whether AQP4 particpates in the psychological dependence induced by morphine remains unclear. In the present study, the effects of AQP4 on the psychological dependence on morphine and the possible mechanism are investigated.In mouse conditioned-place preference (CPP) model, morphine (10 mg/kg, sc, 8d) induced the acquisition of CPP, whlie AQP4 knockout attenuated the acquisition of morphine-indece CPP. In the CPP model, we found that BrdU-positive cells number in hippocampus of morphine-dependent wild-type mice was down-regulated by 26% by using immunohistochemistry assay. But in morphine-dependent AQP4 knockout mice, the Brdu-positive cells number was down-regulated only by 10%. It suggested that AQP4 knockout attenuated the inhibition to the proliferation of hippocampal neural stem cells. The differentiation of newly formed cells was analyzed by double labeling for mature neurons with BrdU and neuron specific unclear protein (NeuN). We found that AQP4 knockout suppressed the decrease in quatity of hippocampal surviving BrdU-positive cells induced by chronic morphine treatment, but the survival rate had no significant change. In addition, the population of surviving BrdU-positive cells essentially matured into neurons, but the phenotypic expression pattern remained unchanged between groups. The phosphorylation of ERK1/2 and CREB in the hippocampus was also studied. We found that chronic morphine treatment did not markedly affect the phosphorylation of ERK1/2 in both wild-type and AQP4 knockout mice. However, chronic morphine treatment reduced the phosphorylation of CREB in wild-type mice, and AQP4 knockout attenuated the morphine-induced decrease in CREB phosphorylation. These results suggested that AQP4 knockout attenuating the inhibition to hippocampal neurogenesis induced by chronic exposure to morphine might be related to its modulating CREB phosphorylation.In conclusion, our studies demonstrated that AQP4 knockout attenuated the acquisition of morphine-induced CPP, and the mechanism might be related to its modulating hippocampal neurogenesis.