¹Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr JM Saavedra, Section on Pharmacology, DIRP, National Institute of Mental Health, National Institutes of Health, DHHS, 10 Center Drive, MSC 1514, Building 10, Room 2D-57, Bethesda, MD 20892, USA. Tel: +1 301 496 0160; Fax: +1 301 402 0337; E-mail: Saavedrj@mail.nih.gov

Received 17 May 2005; Revised 29 July 2005; Accepted 25 August 2005; Published online 5 October 2005.

Abstract

Long-term pretreatment with an angiotensin II AT₁ antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic–pituitary–adrenal responses to isolation stress. We determined whether AT₁ receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT₁ antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT₁ receptor blockade prevented the isolation-induced increase in brain AT₁ receptors and decrease in AT₂ binding in the locus coeruleus. AT₁ receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT₁ receptor antagonist completely prevented the decrease in cortical CRF₁ receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF₁ receptors and the GABA_A complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT₁ receptor antagonists. We propose that AT₁ receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.