BRAIN VASCULAR ALTERATIONS IN NEUROADAPTATIVE RESPONSES: AT1 RECEPTORS AS A RELEVANT TARGET

MARCHESE, N.A.; OCCHIEPPO. V.B.; BASMADJIAN, O.M.; ARMONELLI, S; BREGONZIO, C.

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2018

Sociedad Argentina de Investigación Clínica

Amphetamine exposure is validated as a pharmacological tool to resemble several psychiatric diseases, such as the dopaminergic/glutamatergic imbalance in schizophrenia and mania. However, its effects extend beyond neurotransmission, as psychostimulant exposure has been associated to brain vascular damage and neuroinflammation. Angiotensin II AT1 receptors (AT1-R) are implicated in brain micro-vascular physiological responses; whereas their over-expression is related to inflammatory mediators release, oxidative damage, and endothelial dysfunction in pathological conditions. Using adult Wistar rats exposed to an amphetamine-induced behavioral and neurochemical sensitization protocol, pretreated with an AT1-R antagonist, we analyzed detrimental consequences involving: blood brain barrier (BBB) permeability, microvessels rearrangement, glial reactivity and behavioral performance. For these purpose astroglia and microglia activation was assessed with immunolabeling against GFAP and CD11b, respectively. The vascular alterations were analyzed using von willebrand factor for vascular rearrangement at brain level and in isolated microvessels AT1-R, lipid peroxidation and HSP70 expression were determined. The animals? performances were tested on Y-maze, Holeboard and Hot plate. The BBB permeability was analyzed using an Evans blue technique. Our results showed that amphetamine induced: -Evans blue leakage in hippocampus, -increased glial reactivity and microvessel rearrangement at prelimbic prefrontal and somatosensory cortex,- AT1-R increased expression and cellular stress in isolated microvessels, -working memory deficit and altered perception. Remarkably, our results showed prevention of amphetamine-induced working memory deficit by AT1-R blockade in line with absence of glial and vascular alterations over prelimbic prefrontal cortex. Similarly, AT1-R antagonism prevented amphetamine- induced structural modifications in somatosensory cortex along with altered thermal nociception. The neuroadaptative responses, evoked by the psychostimulant and depending on AT1-R, might resemble some features described for neurodegenerative pathologies, as they involve neuroinflammation and vascular rearrangement, with local vulnerability in cortical areas. In this way, our contribution supports the dysregulation of central Angiotensin II as trigger for neurovascular unit alterations underlying brain disorders