Stress-related disorders are extremely complex and current treatment strategies have limitations. The present study investigated alternative pathological mechanisms using a combination of multiple environmental approaches with biochemical and molecular tools. The aim of the present study was to evaluate blood-brain-barrier (BBB) integrity in socially manipulated animal housing conditions. Multiple environmentally-related models were employed in the current study. The main model proposed (chronically isolated rats) was biochemically validated using the level of peripheral corticosterone. The current study examined and compared the mRNA levels of certain inflammatory and BBB markers in the hippocampal tissue of chronically isolated rats, including claudin-5 ( cldn5 ) and tight junction protein ( tjp ). Animals were divided into four groups: i) Standard housed rats (controls); ii) chronically isolated rats; iii) control rats treated with fluoxetine, which is a standard selective serotonin reuptake inhibitor; and iv) isolated rats treated with fluoxetine. To further examine the effect of environmental conditions on BBB markers, the current study assessed BBB markers in enriched environmental (EE) housing and short-term isolation conditions. The results demonstrated a significant increase in cldn5 and tjp levels in the chronically isolated group. Despite some anomalous results, alterations in mRNA levels were further confirmed in EE housing conditions compared with chronically isolated rats. This trend was also observed in rats subjected to short-term isolation compared with paired controls. Additionally, levels of IL-6, an inflammatory marker associated with neuroinflammation, were markedly increased in the isolated group. However, treatment with fluoxetine treatment reversed these effects. The results indicated that BBB integrity may be compromised in stress-related disorders, highlighting a need for further functional studies on the kinetics of BBB in stress-related models.