Vias neuroinflamatórias envolvidas no transtorno por uso de cocaína

Abstract

INTRODUCTION: Different data suggest that glial cells may participate in drug addiction processes, since they respond to neurochemical changes induced by psychostimulants. Indeed, previous reports have shown that cocaine binds in the complex MD-2/TLR4, being recognized as an exogenous substance and leading to neuroinflammation. However, the role of microglia activation and TLR4 in cocaine induced behavioral abnormalities is still poorly understood. METHODS: Mice were treated with cocaine and MPLA and submitted to microglia phenotypic and inflammation analysis by flow cytometry. Mice were treated with microglial depletor PLX3397 (40 mg/kg, during 7 and subjected to behavioral sensitization induced by cocaine (15 mg/kg, i.p.). Thereafter, they were euthanized and had their brain removed for analysis of number and morphology of microglia cells, as well as quantification of CX3CL1 and BDNF levels in the brain. In addition, mice treated with the TLR4 receptor biased agonist MPLA (50 μg/kg, i.p.) during two days or TLR4-/- mice were submitted to behavioral sensitization. In addition, the inflammasome/caspase pathway and the kynurenine pathway are important for the control of inflammatory processes and the immunological activity of microglial cells. In the present work, we used pharmacological and genetic tools to identify the role of these pathways in behavioral, biochemical and histological changes induced by cocaine in mice. RESULTS: PLX3397 treatment reduced Iba-1+ cells and attenuated behavioral sensitization. In the partial depletion group, the drug also increased activation of remaining microglia cells. Animals treated with PLX3397 + cocaine showed altered CX3CL1 in the striatum, hippocampus and in the PFC, as well as BDNF, in comparison with the animals treated with only cocaine. Besides, CX3CL1 and BDNF levels presented a correlation among the cocaine- induced behavioral sensitization. Moreover, MPLA treatment reduced cocaine-induced hyperlocomotion, while TLR4-/- mice showed an increase in cocaine-induced locomotor activity compared to WT animals. There are different microglia populations between saline, cocaine and cocaine + MPLA treated animals, with differences in the expression of CX3CR1, CD62L, CD11b, CD44, CD11c, Single H and P2RY12. In addition, cocaine increased monocyte number and activation (Ly6C+), increased lymphocytes TCD8+ and TCD4+ central memory, but not effector memory, which was prevented by MPLA. Cocaine also decreased the dendritic spine in the brain, which was also prevented by MPLA. Finally, inhibition of the inflammasome and caspase pathways, reduces cocaine-induced sensitization without altering conditioned place preference. On the other hand, inhibition of the kynurenine pathway reduces both cocaine-induced sensitization and conditioned place preference. CONCLUSION: Considering this data, we suggest that microglia participates in the alterations that occur in neurobiology of cocaine addiction may through TLR4 activation.