Angiotensin Type 1 Receptor Antagonists—A Novel Approach to Augmenting Posttraumatic Stress Disorder and Phobia Therapies?

Abstract

The renin-angiotensin system system, which includes the renin and angiotensin-converting enzyme pathways, and its primary effector peptide angiotensin II (AII) acting through its two cognate receptors, AT1 and AT2 receptors, has been known for 70 years as a major regulator of vascular tone and fluid metabolism (1). Angiotensin receptor blockers (ARBs), consisting of a group of orally active drugs such as losartan (the group is often referred to as the “sartans”), and angiotensinconverting enzyme inhibitors are currently mainstream treatments for essential hypertension and some aspects of diabetes. In addition to these peripheral effects, AII and AT1 receptors are widely distributed in the brain and are being implicated in the regulation of many brain functions, including cerebral circulation, inflammation, neuroendocrine responses, learning, and memory (2). Because many ARBs are already on the market and have a good safety record with long-term use, they would be particularly attractive candidates to be used as novel treatments for central nervous system disorders where current therapies are inadequate. The article by Marvar et al. (3) in this issue of Biological Psychiatry may provide a strong impetus to consider testing ARBs, particularly as an adjunct therapy to augment cognitive-behavioral therapy, in posttraumatic stress disorder (PTSD) and phobias. The idea that ARBs may have some beneficial effects for patients with PTSD first arose from a correlational finding in an epidemiologic study, where veterans treated with ARBs for their medical conditions appeared to develop a less severe form of PTSD compared with veterans who were not taking ARBs (4). Although such correlations may turn out to be spurious, Marvar et al. decided to test whether the beneficial effect of ARBs is mechanistically demonstrable using preclinical models. There are robust animal models that can be used to study the basic circuits and phenotypes involved in PTSD symptoms. Using a standard auditory-cue paired conditioned fear model in mice, Marvar et al. tested the effects of single and multiple doses of selective AT1 antagonist losartan on fear extinction behavior, gene expression changes in the brain, and neuroendocrine and cardiovascular responses. They found that losartan treatment enhanced the consolidation of fear extinction without affecting acquisition, baseline anxiety, blood pressure, and neuroendocrine stress measures. Mice treated with losartan for 2 weeks also demonstrated reduced amygdala AT1 receptor messenger RNA (mRNA) levels. The authors concluded that AT1 receptor antagonism does have potential beneficial effects in a preclinical model of PTSD symptoms and could enhance the extinction of fear memories in PTSD.