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

• Published in: Frontiers in pharmacology Vol. 12; p. 647747
• Main Authors: Basmadjian, Osvaldo M., Occhieppo, Victoria B., Marchese, Natalia A., Silvero C., M. Jazmin, Becerra, María Cecilia, Baiardi, Gustavo, Bregonzio, Claudia
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 03-05-2021
• Subjects: amphetamine; angiogeneis; AT1 receptor; glia; oxidative stress; Pharmacology; working memory
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2021.647747

Background:
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 (AT
1
-R) mediate deleterious effects, such as oxidative/inflammatory responses, endothelial dysfunction, neuronal oxidative damage, alterations that overlap with those observed from AMPH exposure.
Aims:
The aim of this study was to evaluate the AT
1
-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 AT
1
-R in the AMPH-induced short-term memory and working memory deficit.
Methods:
Male Wistar rats were repeatedly administered with the AT
1
-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.
Results:
AMPH induced acute oxidative stress, long-lasting glial reactivity in the PFC and a working memory deficit that were prevented by AT
1
-R blockade pretreatment. Moreover, AMPH induces transient angiogenesis in PFC via AT
1
-R. AMPH did not affect short-term memory.
Conclusion:
Our results support the protective role of AT
1
-R blockade in AMPH-induced oxidative stress, transient angiogenesis and long-lasting glial activation, preserving working memory performance.