A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding.
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.
Saavedra
Juan M
JM
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. Saavedrj@mail.nih.gov
Armando
Ines
I
Bregonzio
Claudia
C
Juorio
Augusto
A
Macova
Miroslava
M
Pavel
Jaroslav
J
Sanchez-Lemus
Enrique
E
D029845:Amphibian Proteins; D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D001562:Benzimidazoles / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002540:Cerebral Cortex / Q000187:drug effects*; D004195:Disease Models, Animal; D005445:Flunitrazepam / Q000493:pharmacokinetics; D018757:GABA Modulators / Q000493:pharmacokinetics; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D012934:Social Isolation / Q000523:psychology*; D013312:Stress, Physiological / Q000188:drug therapy* / Q000503:physiopathology; D013777:Tetrazoles / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D029845:Amphibian Proteins; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018757:GABA Modulators; D036361:Peptide Hormones; D010455:Peptides; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D013777:Tetrazoles; C103016:antalarmin; D000804:Angiotensin II; D001569:Benzodiazepines; D000099052:CRF Receptor, Type 1; D005445:Flunitrazepam; C025727:sauvagine; D014446:Tyrosine 3-Monooxygenase; C081643:candesartan