Amphetamine Induces Oxidative Stress, Glial Activation and Transient Angiogenesis in Prefrontal Cortex via AT1-R

Abstract

<b>Background:</b> Amphetamine (AMPH) alters neurons, glia and microvessels, which affects neurovascular unit coupling, leading to disruption in brain functions such as attention and working memory. Oxidative stress plays a crucial role in these alterations. The angiotensin type I receptors (AT₁-R) mediate deleterious effects, such as oxidative/inflammatory responses, endothelial dysfunction, neuronal oxidative damage, alterations that overlap with those observed from AMPH exposure. <b>Aims:</b> The aim of this study was to evaluate the AT₁-R role in AMPH-induced oxidative stress and glial and vascular alterations in the prefrontal cortex (PFC). Furthermore, we aimed to evaluate the involvement of AT₁-R in the AMPH-induced short-term memory and working memory deficit. <b>Methods:</b> Male Wistar rats were repeatedly administered with the AT₁-R blocker candesartan (CAND) and AMPH. Acute oxidative stress in the PFC was evaluated immediately after the last AMPH administration by determining lipid and protein peroxidation. After 21 off-drug days, long-lasting alterations in the glia, microvessel architecture and to cognitive tasks were evaluated by GFAP, CD11b and von Willebrand immunostaining and by short-term and working memory assessment. <b>Results:</b> AMPH induced acute oxidative stress, long-lasting glial reactivity in the PFC and a working memory deficit that were prevented by AT₁-R blockade pretreatment. Moreover, AMPH induces transient angiogenesis in PFC via AT₁-R. AMPH did not affect short-term memory. <b>Conclusion:</b> Our results support the protective role of AT₁-R blockade in AMPH-induced oxidative stress, transient angiogenesis and long-lasting glial activation, preserving working memory performance.