Preclinical studies on the efects of abrupt cessation of selective serotonin reuptake inhibitors (SSRIs), a medication often
prescribed in alcohol use disorder (AUD) patients with depression, results in alcohol consumption escalation after resuming drinking. However, a potential neuroinfammatory component on this escalation remains unexplored despite the immunomodulatory role of serotonin. Here, we utilized a rat model of 14-daily administration of the SSRI fuoxetine (10 mg/kg/day) along alcohol self-administration deprivation to study the efects of fuoxetine cessation on neuroinfammation after
resuming alcohol drinking. Microglial morphology and infammatory gene expression were analyzed in prelimbic cortex,
striatum, basolateral amygdala and dorsal hippocampus. Results indicated that alcohol drinking reinstatement increased
microglial IBA1 immunoreactivity and altered morphometric features of activated microglia (fractal dimension, lacunarity,
density, roughness, and cell area, perimeter and circularity). Despite alcohol reinstatement, fuoxetine cessation modifed
microglial morphology in a brain region-specifc manner, resulting in hyper-ramifed (spatial complexity of branching),
reactive (lower heterogeneity and circularity)-like microglia. We also found that microglial cell area correlated with changes
in mRNA expression of chemokines (Cx3cl1/fractalkine, Cxcl12/SDF1α, Ccl2/MCP1), cytokines (IL1β, IL6, IL10) and
the innate immune toll-like receptor 4 (TLR4) in dorsal hippocampus. Specifcally, TLR4 correlated with microglial spatial
complexity assessed by fractal dimension in striatum, suggesting a role in process branching. (...)
