Angiotensin II and angiotensin-(1–7) neurotransmissions in the medial amygdala differently control cardiovascular and anxiogenic-like responses to stress in rats

Aguilera G Kiss A Luo X (1995) Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. Journal of Neuroendocrinology 7(10): 775–83.

Bader M (2010) Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Annual Review of Pharmacology and Toxicology 50: 439–65.

Baghai TC Binder EB Schule C , et al. (2006) Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Molecular Psychiatry 11(11): 1003–1015.

Barretto-de-Souza L Benini R Reis-Silva LL , et al. (2022) Role of CRF1 and CRF2 receptors in the lateral hypothalamus in cardiovascular and anxiogenic responses evoked by restraint stress in rats: Evaluation of acute and chronic exposure. Neuropharmacology 212: 109061.

Benini R Oliveira LA Gomes-de-Souza L , et al. (2019) Habituation of the cardiovascular responses to restraint stress in male rats: Influence of length, frequency and number of aversive sessions. Stress 22(1): 151–161.

Benini R Oliveira LA Gomes-de-Souza L , et al. (2025) Role of sex and age on cardiovascular and autonomic responses during acute and repeated restraint stress in rats. Psychophysiology 62(5): e70062.

Bennur S Shankaranarayana Rao BS Pawlak R , et al. (2007) Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator. Neuroscience 144(1): 8–16.

Bilodeau MS Leiter JC (2018) Angiotensin 1-7 in the rostro-ventrolateral medulla increases blood pressure and splanchnic sympathetic nerve activity in anesthetized rats. Respiratory Physiology & Neurobiology 247(5): 103–111.

Bosnyak S Jones Emma S Christopoulos A , et al. (2011) Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clinical Science (London, England: 1979) 121(7): 297–303.

Burghi V Fernández NC Gándola YB , et al. (2017) Validation of commercial Mas receptor antibodies for utilization in Western Blotting, immunofluorescence and immunohistochemistry studies. PLoS One 12(8): e0183278.

Busnardo C Barreto-de-Souza L Omena-Giatti L , et al. (2026) Neuroendocrine, behavioral, cardiovascular and autonomic responses to acute and repeated restraint stress in male rats. Autonomic Neuroscience: Basic & Clinical 263: 103375.

Campagnole-Santos MJ Peliky Fontes MA Verano-Braga T , et al. (2025) ACE2/Angiotensin-(1-7)/Mas and the brain. Brain Research 1863: 149739.

Carobrez AP Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: The elevated plus-maze model 20 years on. Neuroscience & Biobehavioral Reviews 29(8): 1193–1205.

Chai SY Mendelsohn FAO Paxinos G (1987) Angiotensin converting enzyme in rat brain visualized by quantitative in vitro autoradiography. Neuroscience 20(2): 615–627.

Cohen BE Edmondson D Kronish IM (2015) State of the art review: Depression, stress, anxiety, and cardiovascular disease. American Journal of Hypertension 28(11): 1295–1302.

Cooper MA Hooker MK Whitten CJ , et al. (2023) Dominance status modulates activity in medial amygdala cells with projections to the bed nucleus of the stria terminalis. Behavioural Brain Research 453: 114628.

Correa BHM Becari L Fontes MAP , et al. (2022) Involvement of the Renin-angiotensin system in stress: State of the art and research perspectives. Current Neuropharmacology 20(6): 1212–1228.

Costa-Ferreira W Gomes-de-Souza L Crestani CC (2019) AT2 and MAS (but not AT1) angiotensinergic receptors in the medial amygdaloid nucleus modulate the baroreflex activity in rats. Pflügers Archiv: European Journal of Physiology 471(9): 1173–1182.

Costa-Ferreira W Gomes-de-Souza L Crestani CC (2021) Role of angiotensin receptors in the medial amygdaloid nucleus in autonomic, baroreflex and cardiovascular changes evoked by chronic stress in rats. European Journal of Neuroscience 53(3): 763–777.

Costa-Ferreira W Vieira JO Almeida J , et al. (2016) Involvement of type 1 Angiotensin II receptor (AT1) in cardiovascular changes induced by chronic emotional stress: Comparison between homotypic and heterotypic stressors. Frontiers in Pharmacology 7: 262.

Crane JW French KR Buller KM (2005) Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress. Stress (Amsterdam, Netherlands) 8(3): 199–211.

Crestani CC Alves FHF Tavares RF , et al. (2009) Role of the bed nucleus of the stria terminalis in the cardiovascular responses to acute restraint stress in rats. Stress 12(3): 268–278.

Cullinan WE Herman JP Battaglia DF , et al. (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64(2): 477–505.

Davern PJ Chen D Head GA , et al. (2009) Role of Angiotensin II type 1A receptors in cardiovascular reactivity and neuronal activation after aversive stress in mice. Hypertension 54(6): 1262–1268.

Davern PJ Head GA (2011) Role of the medial amygdala in mediating responses to aversive stimuli leading to hypertension. Clinical and Experimental Pharmacology and Physiology 38(2): 136–143.

de Almeida DO Ferreira HS Pereira LB , et al. (2015) Hypertensive response to stress: The role of histaminergic H1 and H2 receptors in the medial amygdala. Physiology & Behavior 144: 95–102.

de Kloet AD Cahill KM Scott KA , et al. (2020) Overexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice. Physiology & Behavior 224(6): 113002.

de Kloet AD Wang L Ludin JA , et al. (2016) Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system. Brain Structure and Function 221(2): 891–912.

Ebner K Rupniak NM Saria A , et al. (2004) Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proceedings of the National Academy of Sciences of the United States of America 101(12): 4280–4285.

Emdin CA Odutayo A Wong CX , et al. (2016) Meta-analysis of anxiety as a risk factor for cardiovascular disease. American Journal of Cardiology 118(4): 511–519.

Fassini A Scopinho AA Fortaleza EAT , et al. (2021) κ-Opioid receptors in the medial amygdaloid nucleus modulate autonomic and neuroendocrine responses to acute stress. European Neuropsychopharmacology 43: 25–37.

Fortaleza EAT Scopinho AA Corrêa FMA (2012a) β-Adrenoceptors in the medial amygdaloid nucleus modulate the tachycardiac response to restraint stress in rats. Neuroscience 227: 170–179.

Fortaleza EAT Scopinho AA de Aguiar Corrêa FM (2012b) α1 and α2-adrenoceptors in the medial amygdaloid nucleus modulate differently the cardiovascular responses to restraint stress in rats. Pharmacological Research 66(2): 154–162.

Fortaleza EAT Tavares RF Corrêa FMA (2009) The medial amygdaloid nucleus modulates cardiovascular responses to acute restraint in rats. Neuroscience 159(2): 717–726.

Freund M Walther T von Bohlen und Halbach O (2012) Immunohistochemical localization of the angiotensin-(1–7) receptor Mas in the murine forebrain. Cell and Tissue Research 348(1): 29–35.

Furlong TM McDowall LM Horiuchi J , et al. (2014) The effect of air puff stress on c-Fos expression in rat hypothalamus and brainstem: central circuitry mediating sympathoexcitation and baroreflex resetting. European Journal of Neuroscience 39(9): 1429–1438.

Galandrin S Denis C Boularan C , et al. (2016) Cardioprotective Angiotensin-(1-7) peptide acts as a natural-biased ligand at the Angiotensin II type 1 receptor. Hypertension (Dallas, Tex.: 1979) 68(6): 1365–1374.

Gomes Da Silva AQ Sousa Dos Santos RA Peliky Fontes MA (2005) Blockade of endogenous angiotensin-(1-7) in the hypothalamic paraventricular nucleus reduces renal sympathetic tone. Hypertension (Dallas, Tex.: 1979) 46(2): 341–348.

Gomes-de-Souza L Bianchi PC Costa-Ferreira W , et al. (2021) CB1 and CB2 receptors in the bed nucleus of the stria terminalis differently modulate anxiety-like behaviors in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry 110: 110284.

Goulart MT Busnardo C Belém-Filho IJA , et al. (2022) NMDA receptors in the insular cortex modulate cardiovascular and autonomic but not neuroendocrine responses to restraint stress in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry 119: 110598.

Gray M Bingham B Viau V (2010) A comparison of two repeated restraint stress paradigms on hypothalamic-pituitary-adrenal axis habituation, gonadal status and central neuropeptide expression in adult male rats. Journal of Neuroendocrinology 22(2): 92–101.

Gray M Innala L Viau V (2014) Central vasopressin V1A receptor blockade alters patterns of cellular activation and prevents glucocorticoid habituation to repeated restraint stress exposure. The International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 17(12): 2005–2015.

Hafko R Villapol S Nostramo R , et al. (2013) Commercially available Angiotensin II At2 receptor antibodies are nonspecific. PLoS One 8(7) e69234.

Hall JE (2003) Historical perspective of the renin-angiotensin system. Molecular Biotechnology 24(1): 27–39.

Herrera M Sparks MA Alfonso-Pecchio AR , et al. (2013) Lack of specificity of commercial antibodies leads to misidentification of angiotensin type 1 receptor protein. Hypertension (Dallas, Tex.: 1979) 61(1): 253–258.

Higuchi S Ohtsu H Suzuki H , et al. (2007) Angiotensin II signal transduction through the AT1 receptor: Novel insights into mechanisms and pathophysiology. Clinical Science 112(7–8): 417–428.

Holman EA (2012) Acute stress and cardiovascular health: Is there an ACE gene connection? Journal of Traumatic Stress 25(5): 592–597.

Jackson JL Leslie CE Hondorp SN (2018) Depressive and anxiety symptoms in adult congenital heart disease: Prevalence, health impact and treatment. Progress in Cardiovascular Diseases 61(3–4): 294–299.

Karnik SS Singh KD Tirupula K , et al. (2017) Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPCRs to the renin-angiotensin system: IUPHAR Review 22. British Journal of Pharmacology 174(9): 737–753.

Karnik SS Unal H Kemp JR , et al. (2015) International union of basic and clinical pharmacology. XCIX. Angiotensin receptors: Interpreters of pathophysiological angiotensinergic stimuli [corrected]. Pharmacological Reviews 67(4): 754–819.

Kivimäki M Steptoe A (2018) Effects of stress on the development and progression of cardiovascular disease. Nature Reviews Cardiology 15(4): 215–229.

Kubo T Okatani H Nishigori Y , et al. (2004) Involvement of the medial amygdaloid nucleus in restraint stress-induced pressor responses in rats. Neuroscience Letters 354(1): 84–86.

Lenkei Z Palkovits M Corvol P , et al. (1997) Expression of Angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: A functional neuroanatomical review. Frontiers in Neuroendocrinology 18(4): 383–439.

Leong DS Terrón JA Falcón-Neri A , et al. (2002) Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT(1A), AT(1B) and AT(2) receptors. Neuroendocrinology 75(4): 227–40.

Li P Zhang F Sun HJ , et al. (2015) Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats. Journal of the American Society of Hypertension 9(11): 865–877.

Liu J Garza JC Li W , et al. (2013) Melanocortin-4 receptor in the medial amygdala regulates emotional stress-induced anxiety-like behaviour, anorexia and corticosterone secretion. The International Journal of Neuropsychopharmacology 16(01): 105–120.

Lynch KR Hawelu-Johnson CL Guyenet PG (1987) Localization of brain angiotensinogen mRNA by hybridization histochemistry. Brain Research 388(2): 149–58.

Marchi-Coelho C Costa-Ferreira W Reis-Silva LL , et al. (2021) Angiotensinergic neurotransmissions in the medial amygdala nucleus modulate behavioral changes in the forced swimming test evoked by acute restraint stress in rats. Cells 10(5): 1217.

McDougall SJ Roulston CA Widdop RE , et al. (2000) Characterisation of vasopressin V1A, angiotensin AT1 and AT2 receptor distribution and density in normotensive and hypertensive rat brain stem and kidney: Effects of restraint stress11Published on the World Wide Web on 2 October 2000. Brain Research 883(1): 148–156.

Mechiel Korte S De Boer SF (2003) A robust animal model of state anxiety: Fear-potentiated behaviour in the elevated plus-maze. European Journal of Pharmacology 463(1–3): 163–175.

Melleu FF Canteras NS (2025) Neural circuits of fear and anxiety: Insights from a neuroethological perspective. Physiology (Bethesda) 40(3): 208–223.

Milik E Cudnoch-Jedrzejewska A Szczepanska-Sadowska E (2016) Effect of chronic mild stress on AT1 receptor messenger RNA expression in the brain and kidney of rats. Psychosomatic Medicine 78(2): 208–220.

Moreno-Santos B Marchi-Coelho C Costa-Ferreira W , et al. (2021) Angiotensinergic receptors in the medial amygdaloid nucleus differently modulate behavioral responses in the elevated plus-maze and forced swimming test in rats. Behavioural Brain Research 397: 112947.

Mozhui K Karlsson RM Kash TL , et al. (2010) Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. Journal of Neuroscience 30(15): 5357–5367.

Myers B (2017) Corticolimbic regulation of cardiovascular responses to stress. Physiology & Behavior 172: 49–59.

Nylocks KM Michopoulos V Rothbaum AO , et al. (2015) An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics 168(4): 307–315.

Oliveira LA Almeida J Benini R , et al. (2015) CRF 1 and CRF 2 receptors in the bed nucleus of the stria terminalis modulate the cardiovascular responses to acute restraint stress in rats. Pharmacological Research 95–96: 53–62.

Oscar CG Müller-Ribeiro FCDF de Castro LG , et al. (2015) Angiotensin-(1–7) in the basolateral amygdala attenuates the cardiovascular response evoked by acute emotional stress. Brain Research 1594: 183–189.

Patel S Hussain T (2020) Synergism between Angiotensin receptors ligands: Role of Angiotensin-(1-7) in modulating AT2 R agonist response on nitric oxide in kidney cells. Pharmacology Research & Perspectives 8(6): e00667.

Paxinos G Watson C (1997) The Rat Brain in Stereotaxic Coodinates

Pellow S Chopin P File SE , et al. (1985) Validation of open: Closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods 14(3): 149–167.

Prakash N Abu Irqeba A Corbin JG (2025) Development and function of the medial amygdala. Trends in Neurosciences 48(1): 22–32.

Remodeling V Griendling KK Busse R , et al. (2006) Signaling by the Angiotensin-converting enzyme. Circulation Research 98(7): 887–896.

Rozanski A Blumenthal JA Kaplan J (1999) Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99(16): 192–217.

Saavedra JM (2017) Beneficial effects of Angiotensin II receptor blockers in brain disorders. Pharmacological Research 125: 91–103.

Saavedra JM (2021) Angiotensin receptor blockers are not just for hypertension anymore. Physiology 36(3): 160–173.

Saavedra JM Armando I (2018) Angiotensin II AT2 receptors contribute to regulate the sympathoadrenal and hormonal reaction to stress stimuli. Cellular and Molecular Neurobiology 38(1): 85–108.

Saavedra JM Sánchez-Lemus E Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. Psychoneuroendocrinology 36(1): 1–18.

Santos CE Benini R Crestani CC (2020) Spontaneous recovery, time course, and circadian influence on habituation of the cardiovascular responses to repeated restraint stress in rats. Pflügers Archiv: European Journal of Physiology 472(10): 1495–1506.

Santos RAS Ferreira AJ Verano-Braga T , et al. (2013) Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: New players of the renin–angiotensin system. Journal of Endocrinology 216(2): R1–R17.

Santos RAS Sampaio WO Alzamora AC , et al. (2018) The ACE2/Angiotensin-(1-7)/MAS axis of the renin-angiotensin system: Focus on Angiotensin-(1-7). Physiological Reviews 98(1): 505–553.

Santos RAS Simoes e Silva AC Maric C , et al. (2003) Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences of the United States of America 100(14): 8258–8263.

Struijs SY de Jong PJ Jeronimus BF , et al. (2021) Psychological risk factors and the course of depression and anxiety disorders: A review of 15 years NESDA research. Journal of Affective Disorders 295: 1347–1359.

Szuhany KL Simon NM (2022) Anxiety disorders: A review. JAMA 328(24): 2431–2445.

Tikhonova MA Amstislavskaya TG Belichenko VM , et al. (2018) Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties. BMC Neuroscience 19(Suppl 1): 13.

Vaccarino V Bremner JD (2024) Stress and cardiovascular disease: an update. Nature Reviews Cardiology 21(9): 603–616.

Vianna DML Carrive P (2005) Changes in cutaneous and body temperature during and after conditioned fear to context in the rat. The European Journal of Neuroscience 21(9): 2505–12.

Vieira JO Duarte JO Costa-Ferreira W , et al. (2018) Sex differences in cardiovascular, neuroendocrine and behavioral changes evoked by chronic stressors in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry 81: 426–437.

von Bohlen und Halbach O (2005) The renin-angiotensin system in the mammalian central nervous system. Current Protein & Peptide Science 6(4): 355–371.

Wang L De Kloet AD Pati D , et al. (2016) Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 105(3): 114–123.

Xue B Yu Y Wei SG , et al. (2019) Stress-induced sensitization of Angiotensin II hypertension is reversed by blockade of angiotensin-converting enzyme or tumor necrosis factor-α. American Journal of Hypertension 32(9): 909–917.

Yu XJ Miao YW Li HB , et al. (2019a) Blockade of endogenous Angiotensin-(1-7) in hypothalamic paraventricular nucleus attenuates high salt-induced sympathoexcitation and hypertension. Neuroscience Bulletin 35(1): 47–56.

Yu Z Swiercz AP Moshfegh CM , et al. (2019b) Angiotensin II type 2 receptor–expressing neurons in the central amygdala influence fear-related behavior. Biological Psychiatry 86(12): 899–909.

Zhu D Tong Q Liu W , et al. (2014) Angiotensin (1–7) protects against stress-induced gastric lesions in rats. Biochemical Pharmacology 87(3): 467–476.