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 (AT₁-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 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.Methods: 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.Results: 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.Conclusion: 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.

Background: The functioning of the central nervous system is complex and it implies tight and coordinated interactions among multiple components. Neurotransmitters systems imbalance is a hallmark in the central nervous system (CNS) disorders. These pathologies profoundly impact the social, cultural, and economic perspective worldwide. The etiopathology of CNS illnesses is still poorly understood, making their treatment difficult. Brain angiotensin II (Ang II), through its AT1 receptors, modulates dopaminergic, glutamatergic and GABAergic neurotransmission, which are responsible for movement control, cognition, emotions and stress responses. Alterations of these functions, concomitant with modified brain reninangiotensin system (RAS) components, have been described in CNS pathologies like depression, Parkinson, Alzheimer, and schizophrenia. In this sense, altered functionality of angiotensin I converting enzyme and AT1 receptors, is associated with augmented susceptibility to the occurrence of these pathologies. Moreover, some epidemiological data showed lower incidence of Alzheimer disease in hypertensive patients under treatment targeting RAS; meanwhile preclinical studies relate RAS with Parkinson and depression. Little is known about schizophrenia and RAS; however, Ang II is closely related to dopamine and glutamate pathways, which are mainly altered in this pathology. Conclusion: The available evidences, together with the results obtained by our group, open the possibility to postulate brain Ang II as a possible therapeutic target to treat the above-mentioned CNS disorders.