Repeated Amphetamine Exposure Blunted Angiotensin II-Induced Responses Mediated by AT1 Receptors.

Abstract

Background: Angiotensin II, is critical in regulating the sympathetic and neuroendocrine systems through angiotensin II type 1 receptors (AT₁-R). Angiotensin II intracerebral administration increases water and sodium intake, as well as renal sodium excretion. Previously, our group has shown that AT₁-R is involved in behavioral and neurochemical sensitization induced by amphetamine. We aimed to assess the physiological output, behavioral, and neurochemical responses to intracerebral angiotensin II administration, via the AT₁-R, twenty-one days after amphetamine administration.

Material and methods: Male Wistar rats received daily vehicle or AT₁-R antagonist (oral) for 10 days, and amphetamine or saline intraperitoneal (i.p.) from day 6 to 10. On day 25 they were implanted with an intracerebral cannula. On day 32, the animals received intracerebral angiotensin II. First group: the animals were tested in a free choice paradigm for 2% NaCl and water intake, and sacrificed for neuronal activity assessment via c-Fos immunohistochemistry. Second group: urine samples were collected for electrolyte determination. Third group: the animals were tested in the plus maze or the hole board for anxiety and working memory evaluation, respectively, and sacrificed for c-Fos immunohistochemistry.

Results: Amphetamine exposure blunted the increase in sodium intake (p = 0.0022), and potentiated the natriuretic (p = 0.0043) and kaliuretic effect (p = 0.0002) induced by angiotensin II. Moreover, amphetamine exposure prevented the expression of the anxiogenic effect (drug effect p < 0.0001) and the memory deficit (p = 0.1314) induced by cerebral angiotensin II administration. Amph decreased c-Fos immunoreactivity in nucleus tractus solitarii (NTS) p = 0.0037; paraventricular nucleus (PVN) p = 0.0047; Central amygdala (CeA) p = 0.0008; Basolateral amygdala (BLA) p = 0.0018; increased in hippocampus region CA1 p = 0.0043; CA3 p = 0.026; and dentate gyrus (DG) p = 0.0057. The blockade of AT₁-R prevented these alterations (sodium intake p = 0.0421 natriuresis p = 0.019; kaliuresis p = 0.196; working memory (p < 0.0001); but no the anxiogenic response to angiotensin II (drug effect p < 0.0001); as well as the c-Fos changes (NTS p = 0.0052; PVN p = 0.029; CeA p = 0.0002; BLA p = 0.0021; CA1 p = 0.0026; CA3 p = 0.022; and DG p = 0.0016).

Conclusion: Most of the long-lasting AT₁-R altered responses to brain angiotensin II administration induced by repeated amphetamine exposure could be prevented by AT₁-R blockade.