Matrix metalloproteinase-9 overexpression in the hippocampus reduces alcohol-induced conditioned-place preference by...

Extracellular matrix proteins appear to be necessary for the synaptic plasticity that underlies addiction memory. In the brain, matrix metalloproteinases (MMPs), especially matrix metalloproteinase-9 (MMP-9), have been recently implicated in processes involving alcohol reward and memory. Here, we showed for the first time, the positive effects of MMP-9 on alcohol-induced conditioned place preference (CPP) behavior and hippocampal neuron plasticity in C57BL/6 mice. Using recombinant adeno-associated viruses to overexpress MMP-9 in the hippocampus, we investigated the NMDAR, PSD-95, and cellular cytoskeleton proteins F-actin/G-actin in the modulation of alcohol reward behavior in mice exposed to CPP. We found that hippocampal infusions of MMP-9 decreased alcohol-induced place preference suggesting a reduction in alcohol reward. Western blot analysis demonstrated that protein expression of NMDA receptors (GluN1, GluN2A and GluN2B) in the hippocampus of alcohol-exposed mice were higher than that of the saline group. Further, the expression of these proteins was decreased in MMP-9 overexpressing mice. MMP-9 also regulated the ratio of F-actin/G-actin (dendritic spines cytoskeleton proteins), which might be the key mediator for behavioral changes in mice. Consequently, our results highlight new evidence that MMP-9 may play an important role in the molecular mechanism underlying alcohol reward and preference.