Inhibition of CSF1R, a receptor involved in microglia viability, alters behavioral and molecular changes induced by cocaine

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.

Microglial homeostasis disruption modulates non-rapid eye movement sleep duration and neuronal activity in adult female mice

“…However, the percentage of depletion we observed is lower than what was previously reported in other studies using a lower dose of PLX3397 through oral gavage (40 mg/kg) (M. Yang et al, 2018). Another team also found a lower depletion rate (around 50%) in the nucleus accumbens of Swiss male mice (da Silva et al, 2021). These discrepancies between studies could be due to depletion efficacy variability between species, sexes and brain regions.…”

Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor PLX3397

“…The low dose of PLX3397 had no effect on microglial density or soma area but significantly increased the total length and maximum length of microglial processes in the male mouse hippocampus. The high dose of PLX3397 significantly increased the intersections of microglial processes in males, which is consistent with a previous report (da Silva et al, 2021). It seems that the low and high doses of PLX3397 do not significantly increase microglial soma size.…”

“…It seems that the low and high doses of PLX3397 do not significantly increase microglial soma size. A recent study reported that PLX3397 can increase the cell body to total cell size ratio of Iba1‐ir cells (da Silva et al, 2021). The results showed that there was no significant difference in microglial density in the hippocampus of mice treated with PLX3397 for between seven and 14 days.…”

Impact of cannabidiol on brain glucose metabolism of C57Bl/6 male mice previously exposed to cocaine

“…These data suggest that CBD had a general effect of reducing microglial activation, but cocaine sensitization avoided this effect. It is known that treatment with cocaine can increase Iba‐1 staining (Burkovetskaya et al., 2020; Cotto et al., 2018; da Silva et al., 2021). Both cocaine use and abstinence affect the expression of regulatory genes necessary for the proper functioning of glial cells, demonstrating the importance of these cells in the adaptive changes that the brain undergoes due to drug exposure (Hayakawa et al., 2008).…”