ANGIOTENSIN II AT1 RECEPTORS MEDIATE NEURONAL SENSITIZATION AND SUSTAINED BLOOD PRESSURE RESPONSE INDUCED BY A SINGLE INJECTION OF AMPHETAMINE

A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT(1) receptors (AT(1)-R) activation, is involved in these responses. However, amphetamine induced alterations can be extended to extra-striatal areas involved in blood pressure control and their physiological outcomes. Our aim for the present study was to analyze the possible role for AT(1)-R in these events using a two injection protocol and to further characterize the proposed AT(1)-R antagonism protocol. Central effect of orally administered AT(1)-R blocker (Candesartan, 3 mg/kg p.o. x 5 days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT(1)-R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5 mg/kg i.p.- day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5 mg/kg i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood pressure response. AT(1)-R blockade decreased LC neurons' spontaneous firing rate. Moreover, sensitized c-Fos immunoreactivity in TH + neurons was found in LC and NTS; and both responses were blunted by the AT(1)-R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor Al. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT(1)-R blockade. Our results extend AT1-R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.