Neurovascular unit alteration in somatosensory cortex and enhancement of thermal nociception induced by amphetamine involves central AT₁ receptor activation

Abstract

The use of psychostimulants, such as amphetamine (Amph), is associated with inflammatory processes, involving glia and vasculature alterations. Brain Angiotensin II (Ang II), through AT -receptors (AT -R), modulates neurotransmission and plays a crucial role in inflammatory responses in brain vasculature and glia. Our aim for the present work was to evaluate the role of AT -R in long-term alterations induced by repeated exposure to Amph. Astrocyte reactivity, neuronal survival and brain microvascular network were analysed at the somatosensory cortex. Thermal nociception was evaluated as a physiological outcome of this brain area. Male Wistar rats (250-320 g) were administered with AT -R antagonist Candesartan/vehicle (3 mg/kg p.o., days 1-5) and Amph/saline (2.5 mg/kg i.p., days 6-10). The four experimental groups were: Veh-Sal, CV-Sal, Veh-Amph, CV-Amph. On day 17, the animals were sacrificed and their brains were processed for Nissl staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) and von Willebrand factor. In another group of animals, thermal nociception was evaluated using hot plate test, in the four experimental groups, on day 17. Data were analysed with two-way anova followed by Bonferroni test. Our results indicate that Amph exposure induces an increase in: neuronal apoptosis, astrocyte reactivity and microvascular network, evaluated as an augmented occupied area by vessels, branching points and their tortuosity. Moreover, Amph exposure decreased the thermal nociception threshold. Pretreatment with the AT -R blocker prevented the described alterations induced by this psychostimulant. The decreased thermal nociception and the structural changes in somatosensory cortex could be considered as extended neuroadaptative responses to Amph, involving AT -R activation.

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

“…Moreover, our results extend the Amph deleterious effects to the microvascular rearrangement in PFC ( Figure 2); supporting their region-specific toxicity as vascular network, modifications are closely related to inflammatory processes (Costa, Incio, & Soares, 2007). Similar vascular alterations have been previously described after Amph exposure (Occhieppo et al, 2017), chronic inflammatory disease (Dorr et al, 2012), and schizophrenia (Katsel, Roussos, Pletnikov, & Haroutunian, 2017).…”

“…Our previous reports support the AT 1 ‐R involvement in the development of Amph‐induced neuroadaptations at neurochemical, structural, and behavioral levels (Paz, Assis, Cabrera, Cancela, & Bregonzio, ; Paz, Marchese, Cancela, & Bregonzio, ; Occhieppo et al, ). Moreover, a long‐lasting overexpression of functional AT 1 ‐R was observed in DA‐innervated areas after Amph exposure (Paz et al, ), whereas altered AT 1 ‐R functionality was described regarding classical AngII‐elicited actions (Casarsa et al, ).…”

“…The vascular architecture analysis (200× magnification) was made as described in a previous report (Occhieppo et al, ). Three parameters were analyzed: (a) percentage of vascular area, (b) number of branching points, and (c) vessels’ tortuosity, calculated as the ratio of the real distance between two consecutive branching points and the shortest distance between them (Figure ).…”

Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis

“…Similarly, although abstinence following chronic amphetamine administration was also shown to increase GFAP immunoreactivity in the dorsal striatum, there was no change in the NAc and PFC [248]. GFAP expression was also increased in the somatosensory cortex after 17 days of abstinence from chronic non-contingent amphetamine administration [249]. In support of these findings, one month or 2 days after administration of a neurotoxic methamphetamine regimen, GFAP expression was persistently increased [250] In brief, although some studies have reported no changes in GFAP expression after withdrawal from amphetamine or methamphetamine treatment, a number of others have shown an increase in GFAP expression.…”

Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?

“…The time taken to shake or lick its paws was considered as the first sign of nociception. A cutoff period of 120 s was set to avoid animal thermal injury (Occhieppo et al., 2017). We considered three variables (a) time taken to feel the stimulus (Initial Time), (b) time taken to escape from the stimulus (Final Time), and (c) the difference between final time and the initial time (Reaction Time).…”