Inhibition of CSF1R, a receptor involved in microglia viability, alters behavioral and molecular changes induced by
Maria Carolina Machado da Silva1, Giovanni Freitas Gomes1, Heliana de Barros Fernandes2,3
1Neuropharmacology Laboratory, Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil.
Abstract:
Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8-9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1+ cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1+ cells, as well as CD68+ and GFAP+ stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction.
Insights
Microglia play a role in cocaine addiction. Inhibiting colony-stimulating factor 1 receptor (CSF1R) in mice altered microglia and reduced cocaine-induced behavioral sensitization, suggesting therapeutic potential.
Area of Science:
- Neuroscience
- Neuroimmunology
- Pharmacology
Background:
- Microglia, the brain's immune cells, are implicated in drug addiction due to their response to neurochemical alterations.
- Understanding microglia's specific role in cocaine addiction is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the involvement of microglia in cocaine-induced behavioral sensitization and molecular changes.
- To evaluate the effects of CSF1R inhibition on microglia and cocaine's impact on the brain.
Main Methods:
- Swiss mice were treated with a CSF1R inhibitor (PLX3397) and subjected to cocaine-induced behavioral sensitization and conditioned place preference.
- Brain tissues were analyzed for morphological, biochemical, and molecular changes in microglia (Iba-1+, CD68+, GFAP+) and related signaling pathways (CX3CL1, CX3CR1, BDNF).
Main Results:
- CSF1R inhibition attenuated cocaine-induced behavioral sensitization and altered microglia morphology, indicating activation.
- Both cocaine and PLX3397 induced glial cell activation markers.
- CSF1R inhibition modulated CX3CL1 and CX3CR1 levels and exacerbated cocaine's reduction of BDNF in the hippocampus.
Conclusions:
- Microglia are integral to the behavioral and molecular effects of cocaine.
- Targeting CSF1R influences microglia activation and may modulate cocaine addiction-related behaviors.
