Glia exerts a strong influence oncocaine-induced plasticity, releasing different mediators that altersexcitatory transmission and neuronal signaling. Previous evidence of our labdemonstrated a central role of microglia in the disruption of glutamate (GLU)homeostasis in the nucleus accumbens (NAc) thought to underlie thestress-induced facilitation of cocaine self-administration. In this project wewill evaluate microglia-dependent mechanisms associated to relapse of cocaineseeking behavior and neurobiological changes. For this purpose, we will use ananimal model of cocaine self-administration administered with minocycline, (apotent inhibitor of microglia activation), in nanoparticles complexed withchitosan (NP-MINO) to facilitate their bioavailability to the brain.Specifically, we will evaluate the effect of NP-MINO on cocaine seekingbehavior, and associated changes such us microglia activation, GLU homeostasis(GLT-1 receptor expression, GLU reuptake and spillover), structuralmodifications in dendritic spines and alterations in synaptic plasticity in theNAc. To carry out these objectives, we will use a combination of molecular,neurochemical and behavioral studies. This novel project will open new avenuestowards the treatment of cocaine addiction. We expect that by restoring glialfunction with NP-MINO it will be possible to normalize the changes in GLUhomeostasis and synaptic plasticity induced by cocaine and, thus, preventdrug-seeking behavior.