, Volume 233, Issue 5, pp 795–807 | Cite as

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations

  • Natalia Andrea Marchese
  • Emilce Artur de laVillarmois
  • Osvaldo Martin Basmadjian
  • Mariela Fernanda PerezEmail author
  • Gustavo Baiardi
  • Claudia Bregonzio
Original Investigation



Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes.


The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events.


Male Wistar rats (250–300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated.


The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade.


AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.


Angiotensin II Amphetamine AT1 receptors Long-term memory Long-term potentiation Hippocampus Inhibitory avoidance FOS Losartan Candesartan 



This study was supported by grants from CONICET 11220120100373CO-KB1, SECyT, FONCyT PRESTAMO BID PICT 2476. The authors are grateful to Estela Salde and Lorena Mercado for their laboratory technical assistance.

Compliance with ethical standards

Conflict of interests

The authors declare that they have no competing interests.

Ethical approval

All procedures were handled in accordance with the NIH Guide for the Care and Use of Laboratory Animals as approved by the Animal Care and Use Committee of the Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina (RES 46 2015).

Supplementary material

213_2015_4153_MOESM1_ESM.doc (52 kb)
Supplementary Table 1 Step-through latencies 1. Statistical distribution values for step-through latencies in the training session of all experimental groups submitted to the passive avoidance test. Values are in seconds. All animals exceeding 60 s were dismissed from the statistical analyses. (DOC 52 kb)
213_2015_4153_MOESM2_ESM.doc (54 kb)
Supplementary Table 2 Fos-immunoreactivity analysis. Overall statistical results (F values) obtained in the two way ANOVA for Fos-IR cells patterns. (DOC 54 kb)


  1. Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:121–145CrossRefPubMedGoogle Scholar
  2. Brown DC, Steward LJ, Ge J, Barnes NM (1996) Ability of angiotensin II to modulate striatal dopamine release via the AT1 receptor in vitro and in vivo. Br J Pharmacol 118:414–420PubMedCentralCrossRefPubMedGoogle Scholar
  3. Bush G, Whalen PJ, Rosen BR, Jenike MA, McInerney SC, Rauch SL (1998) The counting Stroop: an interference task specialized for functional neuroimaging—validation study with functional MRI. Hum Brain Mapp 6:270–282CrossRefPubMedGoogle Scholar
  4. Bush G, Luu P, Posner MI (2000) Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 4:215–222CrossRefPubMedGoogle Scholar
  5. Cabib S, Castellano C (1997) Impairments produced by amphetamine and stress on memory storage are reduced following a chronic stressful experience. Psychopharmacology (Berl) 129:161–167CrossRefGoogle Scholar
  6. Castellano C, Cestari V, Cabib S, Puglisi-Allegra S (1991) Post-training dopamine receptor agonists and antagonists affect memory storage in mice irrespective of their selectivity for D1 or D2 receptors. Behav Neural Biol 56:283–291CrossRefPubMedGoogle Scholar
  7. Cestari V, Castellano C, Cabib S, Puglisi-Allegra S (1992) Strain-dependent effects of post-training dopamine receptor agonists and antagonists on memory storage in mice. Behav Neural Biol 58:58–63CrossRefPubMedGoogle Scholar
  8. Crabbe JC, Alpern HP (1975) d-Amphetamine: disruptive effects on the long-term store of memory and proactive facilitatory effects on learning in inbred mice. Pharmacol Biochem Behav 3:647–652CrossRefPubMedGoogle Scholar
  9. Daubert DL, Meadows GG, Wang JH, Sanchez PJ, Speth RC (1999) Changes in angiotensin II receptors in dopamine-rich regions of the mouse brain with age and ethanol consumption. Brain Res 816:8–16CrossRefPubMedGoogle Scholar
  10. de Souza FA, Sanchis-Segura C, Fukada SY, de Bortoli VC, Zangrossi H, de Oliveira AM Jr (2004) Intracerebroventricular effects of angiotensin II on a step-through passive avoidance task in rats. Neurobiol Learn Mem 81:100–103CrossRefPubMedGoogle Scholar
  11. DeNoble VJ, DeNoble KF, Spencer KR, Chiu AT, Wong PC, Timmermans PB (1991) Non-peptide angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats. Brain Res 561:230–235CrossRefPubMedGoogle Scholar
  12. Dominguez-Meijide A, Villar-Cheda B, Garrido-Gil P, Sierrra-Paredes G, Guerra MJ, Labandeira-Garcia JL (2014) Effect of chronic treatment with angiotensin type 1 receptor antagonists on striatal dopamine levels in normal rats and in a rat model of Parkinson’s disease treated with L-DOPA. Neuropharmacology 76(Pt A):156–168CrossRefPubMedGoogle Scholar
  13. Dwoskin LP, Jewell AL, Cassis LA (1992) DuP 753, a nonpeptide angiotensin II-1 receptor antagonist, alters dopaminergic function in rat striatum. Naunyn Schmiedebergs Arch Pharmacol 345:153–159CrossRefPubMedGoogle Scholar
  14. Eldred KC, Palmiter RD (2013) Amphetamine-induced sensitization has little effect on multiple learning paradigms and fails to rescue mice with a striatal learning defect. PLoS One 8, e59964PubMedCentralCrossRefPubMedGoogle Scholar
  15. Fukushima H, Zhang Y, Archbold G, Ishikawa R, Nader K, Kida S (2014) Enhancement of fear memory by retrieval through reconsolidation. Elife 3, e02736PubMedCentralCrossRefPubMedGoogle Scholar
  16. Gabach LA, Carlini VP, Monti MC, Maglio LE, De Barioglio SR, Perez MF (2013) Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability? Psychopharmacology (Berl) 229:41–50CrossRefGoogle Scholar
  17. Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28:370–490CrossRefPubMedGoogle Scholar
  18. Hoebel BG, Rada P, Mark GP, Hernandez L (1994) The power of integrative peptides to reinforce behavior by releasing dopamine. Ann N Y Acad Sci 739:36–41CrossRefPubMedGoogle Scholar
  19. Ito R, Canseliet M (2010) Amphetamine exposure selectively enhances hippocampus-dependent spatial learning and attenuates amygdala-dependent cue learning. Neuropsychopharmacology 35:1440–1452PubMedCentralCrossRefPubMedGoogle Scholar
  20. James DT (1975) Posttrial d-amphetamine sulfate and one-trail learning in mice. J Comp Physiol Psychol 89:626–635CrossRefPubMedGoogle Scholar
  21. Jenkins TA, Chai SY, Mendelsohn FA (1997) Effect of angiotensin II on striatal dopamine release in the spontaneous hypertensive rat. Clin Exp Hypertens 19:645–658CrossRefPubMedGoogle Scholar
  22. Kaminsky O, Klenerova V, Stohr J, Sida P, Hynie S (2001) Differences in the behaviour of Sprague-Dawley and Lewis rats during repeated passive avoidance procedure: effect of amphetamine. Pharmacol Res 44:117–122CrossRefPubMedGoogle Scholar
  23. Kerns JG, Cohen JD, MacDonald AW 3rd, Cho RY, Stenger VA, Carter CS (2004) Anterior cingulate conflict monitoring and adjustments in control. Science 303:1023–1026CrossRefPubMedGoogle Scholar
  24. Kokkinidis L (1983) The effects of chronic amphetamine administration on the acquisition and extinction of an active and passive avoidance response in mice. Pharmacol Biochem Behav 19:593–598CrossRefPubMedGoogle Scholar
  25. Koller M, Krause HP, Hoffmeister F, Ganten D (1979) Endogenous brain angiotensin II disrupts passive avoidance behavior in rats. Neurosci Lett 14:71–75CrossRefPubMedGoogle Scholar
  26. Labandeira-Garcia JL, Rodriguez-Pallares J, Villar-Cheda B, Rodriguez-Perez AI, Garrido-Gil P, Guerra MJ (2011) Aging, Angiotensin system and dopaminergic degeneration in the substantia nigra. Aging Dis 2:257–274PubMedCentralPubMedGoogle Scholar
  27. Lee EH, Ma YL, Wayner MJ, Armstrong DL (1995) Impaired retention by angiotensin II mediated by the AT1 receptor. Peptides 16:1069–1071CrossRefPubMedGoogle Scholar
  28. Leri F, Nahas E, Henderson K, Limebeer CL, Parker LA, White NM (2013) Effects of post-training heroin and d-amphetamine on consolidation of win-stay learning and fear conditioning. J Psychopharmacol 27:292–301CrossRefPubMedGoogle Scholar
  29. Llano Lopez LH, Caif F, Garcia S, Fraile M, Landa AI, Baiardi G, Lafuente JV, Braszko JJ, Bregonzio C, Gargiulo PA (2012) Anxiolytic-like effect of losartan injected into amygdala of the acutely stressed rats. Pharmacol Rep 64:54–63CrossRefPubMedGoogle Scholar
  30. MacDonald AW 3rd, Cohen JD, Stenger VA, Carter CS (2000) Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 288:1835–1838CrossRefPubMedGoogle Scholar
  31. Martin SJ, Grimwood PD, Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23:649–711CrossRefPubMedGoogle Scholar
  32. Martinez-Pinilla E, Rodriguez-Perez AI, Navarro G, Aguinaga D, Moreno E, Lanciego JL, Labandeira-Garcia JL, Franco R (2015) Dopamine D2 and angiotensin II type 1 receptors form functional heteromers in rat striatum. Biochem Pharmacol 96:131–142CrossRefPubMedGoogle Scholar
  33. McGaugh JL (1973) Drug facilitation of learning and memory. Annu Rev Pharmacol 13:229–241CrossRefPubMedGoogle Scholar
  34. Mendelsohn FA, Jenkins TA, Berkovic SF (1993) Effects of angiotensin II on dopamine and serotonin turnover in the striatum of conscious rats. Brain Res 613:221–229CrossRefPubMedGoogle Scholar
  35. Morgan JI, Curran T (1991) Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 14:421–451CrossRefPubMedGoogle Scholar
  36. Morgan JM, Routtenberg A (1977) Angiotensin injected into the neostriatum after learning disrupts retention performance. Science 196:87–89CrossRefPubMedGoogle Scholar
  37. Narayanaswami V, Somkuwar SS, Horton DB, Cassis LA, Dwoskin LP (2013) Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [(3)H]dopamine and [(3)H]norepinephrine release. Biochem Pharmacol 86:656–665PubMedCentralCrossRefPubMedGoogle Scholar
  38. Nelson A, Killcross S (2006) Amphetamine exposure enhances habit formation. J Neurosci 26:3805–3812CrossRefPubMedGoogle Scholar
  39. Parent A (1990) Extrinsic connections of the basal ganglia. Trends Neurosci 13:254–258CrossRefPubMedGoogle Scholar
  40. Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier, OxfordGoogle Scholar
  41. Paz MC, Assis MA, Cabrera RJ, Cancela LM, Bregonzio C (2011) The AT(1) angiotensin II receptor blockade attenuates the development of amphetamine-induced behavioral sensitization in a two-injection protocol. Synapse 65:505–512CrossRefPubMedGoogle Scholar
  42. Paz MC, Marchese NA, Cancela LM, Bregonzio C (2013) Angiotensin II AT(1) receptors are involved in neuronal activation induced by amphetamine in a two-injection protocol. Biomed Res Int 2013:534817PubMedCentralPubMedGoogle Scholar
  43. Paz MC, Marchese NA, Stroppa MM, Gerez de Burgos NM, Imboden H, Baiardi G, Cancela LM, Bregonzio C (2014) Involvement of the brain renin-angiotensin system (RAS) in the neuroadaptive responses induced by amphetamine in a two-injection protocol. Behav Brain Res 272:314–323CrossRefPubMedGoogle Scholar
  44. Perez MF, Gabach LA, Almiron RS, Carlini VP, De Barioglio SR, Ramirez SR, Ramirez OA (2010) Different chronic cocaine administration protocols induce changes on dentate gyrus plasticity and hippocampal dependent behavior. Synapse 64:742–753PubMedGoogle Scholar
  45. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285CrossRefPubMedGoogle Scholar
  46. Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192–216CrossRefPubMedGoogle Scholar
  47. Puglisi-Allegra S, Cestari V, Cabib S, Castellano C (1994) Strain-dependent effects of post-training cocaine or nomifensine on memory storage involve both D1 and D2 dopamine receptors. Psychopharmacology (Berl) 115:157–162CrossRefGoogle Scholar
  48. Raghavendra V, Chopra K, Kulkarni SK (1999) Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention. Peptides 20:335–342CrossRefPubMedGoogle Scholar
  49. Robbins TW, Ersche KD, Everitt BJ (2008) Drug addiction and the memory systems of the brain. Ann N Y Acad Sci 1141:1–21CrossRefPubMedGoogle Scholar
  50. Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497PubMedGoogle Scholar
  51. Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47(Suppl 1):33–46CrossRefPubMedGoogle Scholar
  52. Saavedra JM (1992) Brain and pituitary angiotensin. Endocr Rev 13:329–380CrossRefPubMedGoogle Scholar
  53. Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, Macova M (2005) Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists. Regul Pept 128:227–238CrossRefPubMedGoogle Scholar
  54. Schmidt ED, Tilders FJ, Binnekade R, Schoffelmeer AN, De Vries TJ (1999) Stressor- or drug-induced sensitization of the corticosterone response is not critically involved in the long-term expression of behavioural sensitization to amphetamine. Neuroscience 92:343–352CrossRefPubMedGoogle Scholar
  55. Seliger DL (1977) Passive avoidance learning in the rat as functions of d-amphetamine dosage and shock intensity. Psychopharmacology (Berl) 54:241–242CrossRefGoogle Scholar
  56. Simon NW, Setlow B (2006) Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: implications for drug addiction. Neurobiol Learn Mem 86:305–310CrossRefPubMedGoogle Scholar
  57. Simonnet G, Giorguieff-Chesselet MF (1979) Stimulating effect of angiotensin II on the spontaneous release of newly synthesized [3H]dopamine in rat striatal slices. Neurosci Lett 15:153–158CrossRefPubMedGoogle Scholar
  58. Teyler TJ, DiScenna P (1987) Long-term potentiation. Annu Rev Neurosci 10:131–161CrossRefPubMedGoogle Scholar
  59. Tilders FJ, Schmidt ED (1999) Cross-sensitization between immune and non-immune stressors. A role in the etiology of depression? Adv Exp Med Biol 461:179–197CrossRefPubMedGoogle Scholar
  60. Tse MT, Cantor A, Floresco SB (2011) Repeated amphetamine exposure disrupts dopaminergic modulation of amygdala-prefrontal circuitry and cognitive/emotional functioning. J Neurosci 31:11282–11294CrossRefPubMedGoogle Scholar
  61. van den Buuse M, Zheng TW, Walker LL, Denton DA (2005) Angiotensin-converting enzyme (ACE) interacts with dopaminergic mechanisms in the brain to modulate prepulse inhibition in mice. Neurosci Lett 380:6–11CrossRefPubMedGoogle Scholar
  62. Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology (Berl) 151:99–120CrossRefGoogle Scholar
  63. Vanderschuren LJ, Schmidt ED, De Vries TJ, Van Moorsel CA, Tilders FJ, Schoffelmeer AN (1999) A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J Neurosci 19:9579–9586PubMedGoogle Scholar
  64. Villar-Cheda B, Rodriguez-Pallares J, Valenzuela R, Munoz A, Guerra MJ, Baltatu OC, Labandeira-Garcia JL (2010) Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson’s disease. Eur J Neurosci 32:1695–1706CrossRefPubMedGoogle Scholar
  65. Villar-Cheda B, Dominguez-Meijide A, Valenzuela R, Granado N, Moratalla R, Labandeira-Garcia JL (2014) Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiol Aging 35:1726–1738CrossRefPubMedGoogle Scholar
  66. White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51:141–153CrossRefPubMedGoogle Scholar
  67. Wolf ME (2002) Addiction: making the connection between behavioral changes and neuronal plasticity in specific pathways. Mol Interv 2:146–157CrossRefPubMedGoogle Scholar
  68. Zhuo J, Moeller I, Jenkins T, Chai SY, Allen AM, Ohishi M, Mendelsohn FA (1998) Mapping tissue angiotensin-converting enzyme and angiotensin AT1, AT2 and AT4 receptors. J Hypertens 16:2027–2037CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Natalia Andrea Marchese
    • 1
  • Emilce Artur de laVillarmois
    • 1
  • Osvaldo Martin Basmadjian
    • 1
  • Mariela Fernanda Perez
    • 1
    Email author
  • Gustavo Baiardi
    • 2
  • Claudia Bregonzio
    • 1
  1. 1.Instituto de Farmacología Experimental Córdoba (IFEC-CONICET) Departamento de FarmacologíaFacultad de Ciencias Químicas Universidad Nacional de CórdobaCórdobaArgentina
  2. 2.Laboratorio de Neurofarmacología, (IIBYT-CONICET)Universidad Nacional de CórdobaCórdobaArgentina

Personalised recommendations