Angiotensin II modulates amphetamine-induced glial and brain vascular responses, and attention deficit via angiotensin type 1 receptor: Evidence from brain regional sensitivity to amphetamine

Amphetamine-induced neuroadaptations involve vascular damage, neuroinflammation, a hypo-functioning prefrontal cortex (PFC), and cognitive alterations. Brain angiotensin II, through angiotensin type 1 receptor (AT(1)-R), mediates oxidative/inflammatory responses, promoting endothelial dysfunction, neuronal oxidative damage and glial reactivity. The present work aims to unmask the role of AT(1)-R in the development of amphetamine-induced changes over glial and vascular components within PFC and hippocampus. Attention deficit was evaluated as a behavioral neuroadaptation induced by amphetamine. Brain microvessels were isolated to further evaluate vascular alterations after amphetamine exposure. Male Wistar rats were administered with AT(1)-R antagonist, candesartan, followed by repeated amphetamine. After one week drug-off period, animals received a saline or amphetamine challenge and were evaluated in behavioral tests. Afterward, their brains were processed for cresyl violet staining, CD11b (microglia marker), GFAP (astrocyte marker) or von Willebrand factor (vascular marker) immunohistochemistry, and oxidative/cellular stress determinations in brain microvessels. Statistical analysis was performed by using factorial ANOVA followed by Bonferroni or Tukey tests. Repeated amphetamine administration increased astroglial and microglial markers immunoreactivity, increased apoptotic cells, and promoted vascular network rearrangement at the PFC concomitantly with an attention deficit. Although the amphetamine challenge improved the attentional performance, it triggers detrimental effects probably because of the exacerbated malondialdehyde levels and increased heat shock protein 70 expression in microvessels. All observed amphetamine-induced alterations were prevented by the AT(1)-R blockade. Our results support the AT(1)-R involvement in the development of oxidative/inflammatory conditions triggered by amphetamine exposure, affecting cortical areas and increasing vascular susceptibility to future challenges.