Abstract P201: Divergent Angiotensin Receptor Signaling in a Mouse Model of Post-Traumatic Stress Disorder (PTSD)

Abstract

Independent of their beneficial effects on hypertension and cardiovascular related disease, angiotensin receptor type 1 (AT1R) blockers can improve stress-related symptoms. AT1R receptor-mediated actions can be counteracted directly or indirectly by the angiotensin receptor type 2 receptor (AT2R). Our recent studies in a mouse model of PTSD have shown that AT1R blockade increases the extinction (learned inhibition) of a traumatic fear memory and that AT1R mRNA expression is reduced in fear related brain regions of animals treated with the AT1R antagonist losartan. These data imply that downstream AT1 signaling events maybe important in consolidation of fear memory extinction. Therefore we investigated the acute effects of AT2R inhibition and AT2R stimulation on fear memory and baseline anxiety in mice. We performed classical Pavlovian fear conditioning pairing auditory cues with foot shocks and examined fear extinction (% freezing to conditioned stimulus) in the presence of the AT2R antagonist PD 123319 and agonist Compound 21. Twenty-four hours following fear conditioning, PD 123319 (15 mg/kg IP), Compound 21 (10 mg/kg IP) or vehicle was administered prior to fear memory extinction. The PD treated group exhibited significantly less percent freezing (68%; 68 of 100) compared to vehicle control (47%; 47 of 100) during fear expression (F10, 300 = 1.9; p<0.05, n=15) while no effect was observed during extinction retention, an index of long-term fear memory. On the other hand, Compound 21 had no effect on fear expression, extinction or basal levels of anxiety. Moreover, following fear conditioning, qPCR data revealed that mRNA expression of AT2R and angiotensin converting enzyme 2 (ACE2) in the central amygdala were elevated (5 fold and 3 fold respectively, P<0.05, n=6) compared to home cage control, however the AT1R and angiotensin converting enzyme (ACE) gene expression pathways were unaltered. PD 123319 and Compound 21 had no effect on basal levels of anxiety as determined by open field testing. These data indicate that AT1R and AT2R may have divergent effects on short and long-term fear memory formation. Further studies are required to understand the differential regulation of angiotensin receptor signaling in PTSD.