title: Angiotensin II AT1receptors mediate neuronal sensitization and sustained blood pressure response induced by a single injection of amphetamine.
abstract: A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT1receptors (AT1-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 AT1-R in these events using a two-injection protocol and to further characterize the proposed AT1-R antagonism protocol. Central effect of orally administered AT1-R blocker (Candesartan, 3mg/kg p.o.×5days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT1-R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5mg/kg i.p. - day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5mg/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. AT1-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 AT1-R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT1-R blockade. Our results extend AT1-R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output.
authors.affiliation: Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: N A
authors.initials: NA
authors.lastname: Marchese
authors.affiliation: Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: M C
authors.initials: MC
authors.lastname: Paz
authors.affiliation: Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: X
authors.initials: X
authors.lastname: Caeiro
authors.affiliation: Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: F M
authors.initials: FM
authors.lastname: Dadam
authors.affiliation: Laboratorio de Neurofarmacología, (IIBYT-CONICET) Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Baiardi
authors.affiliation: Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: M F
authors.initials: MF
authors.lastname: Perez
authors.affiliation: Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: bregonzio@fcq.unc.edu.ar.
authors.forename: C
authors.initials: C
authors.lastname: Bregonzio
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000661:Amphetamine / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D066274:Central Amygdaloid Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D017552:Solitary Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016760:Proto-Oncogene Proteins c-fos; D044140:Receptor, Angiotensin, Type 1; D013566:Sympathomimetics; D000661:Amphetamine
keywords: amphetamine sensitization; angiotensin II AT(1) receptors; blood pressure response; c-Fos/TH immunoreactivity; locus coeruleus; nucleus of the solitary tract