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Background: Angiotensin II, is critical in regulating the sympathetic and neuroendocrine systems through angiotensin II type 1 receptors (AT 1 -R). Angiotensin II intracerebral administration increases water and sodium intake, as well as renal sodium excretion. Previously, our group has shown that AT 1 -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 AT 1 -R, twenty-one days after amphetamine administration., Material and Methods: Male Wistar rats received daily vehicle or AT 1 -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 AT 1 -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 AT 1 -R altered responses to brain angiotensin II administration induced by repeated amphetamine exposure could be prevented by AT 1 -R blockade.

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT 1 receptors (AT 1 -R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT 1 -R role in the development and maintenance of AMPH-induced sensitization. Also, the AT 1 -R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT 1 -R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT 1 -R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT 1 -R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT 1 -R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT 1 -R blockade altered the performance of social interaction. Our results highlight the AT 1 -R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT 1 -R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT 1 -R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: The functioning of the central nervous system is complex and it implies tight and coordinated interactions among multiple components. Neurotransmitters systems imbalance is a hallmark in the central nervous system (CNS) disorders. These pathologies profoundly impact the social, cultural, and economic perspective worldwide. The etiopathology of CNS illnesses is still poorly understood, making their treatment difficult. Brain angiotensin II (Ang II), through its AT1 receptors, modulates dopaminergic, glutamatergic and GABAergic neurotransmission, which are responsible for movement control, cognition, emotions and stress responses. Alterations of these functions, concomitant with modified brain reninangiotensin system (RAS) components, have been described in CNS pathologies like depression, Parkinson, Alzheimer, and schizophrenia. In this sense, altered functionality of angiotensin I converting enzyme and AT1 receptors, is associated with augmented susceptibility to the occurrence of these pathologies. Moreover, some epidemiological data showed lower incidence of Alzheimer disease in hypertensive patients under treatment targeting RAS; meanwhile preclinical studies relate RAS with Parkinson and depression. Little is known about schizophrenia and RAS; however, Ang II is closely related to dopamine and glutamate pathways, which are mainly altered in this pathology., Conclusion: The available evidences, together with the results obtained by our group, open the possibility to postulate brain Ang II as a possible therapeutic target to treat the above-mentioned CNS disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Central nucleus of the amygdala (CeA) is one of the most important regulatory centres for the emotional processes. Among the different neurotransmitter systems present in this nucleus, AT1 receptors have been also found, but their role in the generation and modulation of emotions is not fully understood. The present work evaluated the effect of intra-amygdalar injection of losartan (AT1 receptor antagonist) and angiotensin II (Ang II) in the anxiety state induced by fear-potentiated plus maze in male Wistar rats. Fear in the elevated plus maze can be potentiated by prior inescapable footshock stress. The decrease in the time spent in the open arms induced by the inescapable footshock was totally prevented by losartan (4 pmol) administration in CeA. It was also found that Ang II (48 fmol) administration decreased the time spent in the open arms in animals with or without previous footshock exposure. The locomotor activity and grooming behaviour were also evaluated. The results obtained from the different parameters analyzed allowed us to conclude that the Ang II AT1 receptors in CeA are involved in the anxiety state induced by stress in the fear-potentiated plus-maze behaviour.

Peripheral and brain angiotensin II AT(1) receptor blockade decreases high blood pressure, stress, and neuronal injury. To clarify the effects of long-term brain Ang II receptor blockade, the AT(1) blocker, candesartan, was orally administered to spontaneously hypertensive rats (SHRs) for 40 days, followed by intraventricular injection of 25 ng of Ang II. Before Ang II injection, AT(1) receptor blockade normalized blood pressure and decreased plasma adrenocorticotropic hormone (ACTH) and corticosterone. After central administration of excess Ang II, the reduction of ACTH and corticosterone release induced by AT(1) receptor blockade no longer occurred. Central Ang II administration to vehicle-treated SHRs further increased blood pressure, provoked drinking, increased tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus, and stimulated sympathoadrenal catecholamine release. Pretreatment with the AT(1) receptor antagonist eliminated Ang II-induced increases in blood pressure, water intake, and sympathoadrenal catecholamine release; inhibited peripheral and brain AT(1) receptors; increased AT(2) receptor binding in the locus coeruleus, inferior olive, and adrenal cortex; and decreased AT(2) receptor binding in the adrenal medulla. Inhibition of brain AT(1) receptors correlated with decreased TH transcription in the locus coeruleus, indicating a decreased central sympathetic drive. This, and the diminished adrenomedullary AT(1) and AT(2) receptor stimulation, result in decreased sympathoadrenomedullary stimulation. Oral administration of AT(1) antagonists can effectively block central actions of Ang II, regulating blood pressure and reaction to stress, and selectively and differentially modulating sympathoadrenal response and the hypothalamic-pituitary-adrenal stimulation produced by brain Ang II--effects of potential therapeutic importance.

The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT(1) receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT(1) receptor mRNA expression. The expression of paraventricular AT(1) receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT(1) receptor antagonist blocks peripheral and brain AT(1) receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders.

The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin II type 1 and 2 (AT(1) and AT(2)) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT(1) receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT(1) receptor antagonism prevented the stress-induced increase in adrenomedullary AT(2) receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT(1) receptor or with PD 123319, an AT(2) receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT(1) receptor antagonism decreased the levels of Fra-2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT(2) antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT(1) and AT(2) receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT(1) and AT(2) receptor types.

Cold-restraint stress reduces gastric blood flow and produces acute gastric ulcers. We studied the role of Angiotensin II (Ang II) on gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated for 14 days with the AT(1) receptor antagonist candesartan before cold-restraint stress. AT(1) blockade increased gastric blood flow 40% to 50%; prevented gastric ulcer formation by 70% to 80%; reduced the increase in adrenomedullary epinephrine and TH mRNA without preventing the stress-induced increase in adrenal corticosterone; decreased the stress-induced expression of tumor necrosis factor alpha (TNF-alpha) and adhesion protein ICAM-1 in arterial endothelium, and neutrophil infiltration in the gastric mucosa; and decreased PGE(2) content. AT(1) receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, anti-inflammatory effects with reduction in TNF-alpha, and ICAM-1 expression, leading to reduced neutrophil infiltration while maintaining the protective glucocorticoid effects and PGE(2) release. Ang II has a crucial role, through stimulation of AT(1) receptors, in the production and progression of stress-induced gastric injury, and AT(1) receptor antagonists could be of therapeutic benefit.

A 2-week pretreatment with an Angiotensin II AT(1) antagonist prevented the adrenomedullary and hormonal response to isolation stress. We studied the effect of life-long treatment with the AT(1) receptor antagonist candesartan, 10 mg/kg/day, or vehicle administered orally in the drinking water from 8 weeks of age on the response to stress of stress-sensitive spontaneously hypertensive rats (SHRs) and their normotensive controls, the Wistar Kyoto (WKY). Rats were submitted to 24-h isolation stress at different times during the treatment. Treatment with candesartan extended the lifespan of SHRs. AT(1) receptor blockade retained its capacity to blunt the response to isolation stress over a long period of treatment. The AT(1) antagonist inhibited epinephrine release in SHR but not in WKY rats during the first 3 months, corticosterone release in SHR and WKY rats during 10 months, and vasopressin release in SHR rats during 18 months of treatment when rats were submitted to isolation stress. There were no changes in vasopressin release in WKY rats during stress or after AT(1) receptor blockade. We conclude that the blockade of the stress response by the AT(1) receptor antagonist is long lasting and differs between stress-prone SHR and WKY rats and that the specific components of the stress response (sympathoadrenal activity, hypothalamic-pituitary-adrenal axis activation, and vasopressin release) react differently to AT(1) receptor blockade. The long-term protective effects of AT(1) receptor blockade can be important in animals vulnerable to stress and, in conjunction with the normalization of blood pressure, can prolong lifespan through end-organ protection.

Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT1 receptor antagonist candesartan before cold-restraint stress. AT1 receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT1 blockade increased gastric blood flow by 40-50%, prevented gastric ulcer formation by 70-80% after cold-restraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-alpha and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE2. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects (with reduction in TNF-alpha and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE2 release. Angiotensin II has a crucial role, through stimulation of AT1 receptors, in the production and progression of stress-induced gastric injury, and AT1 receptor antagonists could be of therapeutic benefit.

Cold-restraint stress reduces gastric blood flow and produces acute gastric ulcers. We studied the role of Angiotensin II (Ang II) on gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated for 14 days with the AT1 receptor antagonist candesartan before cold-restraint stress. AT1 blockade increased gastric blood flow 40% to 50%; prevented gastric ulcer formation by 70% to 80%; reduced the increase in adrenomedullary epinephrine and TH mRNA without preventing the stress-induced increase in adrenal corticosterone; decreased the stress-induced expression of tumor necrosis factor (TNF-α) and adhesion protein ICAM-1 in arterial endothelium, and neutrophil infiltration in the gastric mucosa; and decreased PGE2 content. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, anti-inflammatory effects with reduction in TNF-α, and ICAM-1 expression, leading to reduced neutrophil infiltration while maintaining the protective glucocorticoid effects and PGE2 release. Ang II has a crucial role, through stimulation of AT1 receptors, in the production and progression of stress-induced gastric injury, and AT1 receptor antagonists could be of therapeutic benefit. [ABSTRACT FROM AUTHOR]

The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin II type 1 and 2 (AT1 and AT2) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT1 receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT1 receptor antagonism prevented the stress-induced increase in adrenomedullary AT2 receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT1 receptor or with PD 123319, an AT2 receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT1 receptor antagonism decreased the levels of Fra- 2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT2 antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT1 and AT2 receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT1 and AT2 receptor types. [ABSTRACT FROM AUTHOR]

Previous results from our laboratory showed that angiotensin II AT 1 receptors (AT 1 -R) are involved in the neuroadaptative changes induced by amphetamine. The aim of the present work was to study functional and neurochemical responses to angiotensin II (ANG II) mediated by AT 1 -R activation in animals previously exposed to amphetamine. For this purpose male Wistar rats (250–320 g) were treated with amphetamine (2.5 mg/kg/day intraperitoneal) or saline for 5 days and implanted with intracerebroventricular (i.c.v.) cannulae. Seven days after the last amphetamine administration the animals received ANG II (400 pmol) i.c.v. One group was tested in a free choice paradigm for sodium (2% NaCl) and water intake and sacrificed for Fos immunoreactivity (Fos-IR) determinations. In a second group of rats, urine and plasma samples were collected for electrolytes and plasma renin activity determination and then they were sacrificed for Fos-IR determination in Oxytocinergic neurons (Fos-OT-IR). Results: Repeated amphetamine exposure (a) prevented the increase in sodium intake and Fos-IR cells in caudate-putamen and accumbens nucleus induced by ANG II i.c.v. (b) potentiated urinary sodium excretion and Fos-OT-IR in hypothalamus and (c) increased the inhibitory response in plasma renin activity, in response to ANG II i.c.v. Our results indicate a possible functional desensitisation of AT 1 -R in response to ANG II, induced by repeated amphetamine exposure. This functional AT 1 -R desensitisation allows to unmask the effects of ANG II i.c.v. mediated by oxytocin. We conclude that the long lasting changes in brain AT 1 -R functionality should be considered among the psychostimulant-induced neuroadaptations. [ABSTRACT FROM AUTHOR]