The Effects of the Angiotensin II Receptor Antagonist Losartan on Appetitive Versus Aversive Learning: A Randomized Controlled Trial

Abstract

Background: Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves inhibitory learning where the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and might have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown.Methods: We used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. In a double-blind parallel design, healthy volunteers were randomly assigned to single-dose losartan (50mg) (N=28) versus placebo (N=25). Participants then performed a reinforcement learning task which simultaneously probes appetitive and aversive learning. Participant choice behaviour was analysed using both a standard reinforcement learning model and analysis of choice switching behaviour.Results: Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behaviour. Conclusion:This study shows that losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations.

Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory

“…While the clinical efficacy for propranolol as a treatment for PTSD continues to be debated, renewed interest in memory reconsolidation has led to the study of alternative compounds that may be of translational value 41 , 42 . Similar to propranolol, losartan is an FDA-approved drug used to treat high blood pressure, and it appears that AT 1 R inhibition with losartan can modify various central memory processes in normotensive subjects 4 , 8 , 9 . The ability of the RAS to modulate central memory processes may explain early retrospective clinical observations between RAS inhibition and reduced PTSD symptom severity 1 .…”

“…Pre-clinical research demonstrates that peripheral AT 1 R inhibition with losartan 3 – 5 or deletion of AT 1 R from select neuronal populations facilitates fear memory extinction 6 . More recent evidence in humans indicates that losartan improves early threat discrimination and facilitates threat processing 7 , in addition to accelerating fear extinction 8 and modifying aversive learning 9 . Despite these recent observations in both humans and rodents 10 , in addition to earlier literature describing a role for angiotensins in learning and memory 11 , 12 , many of the underlying neurobiological mechanisms remain unknown.…”

Angiotensin involvement in trauma processing—exploring candidate neurocognitive mechanisms of preventing post-traumatic stress symptoms

“…Elucidating the interplay of cognitive and neurochemical mechanisms in disorder development would have tremendous implications for the identification of prevention and treatment targets, yet this relationship remains poorly understood. Recent research increasingly suggests involvement of the renin-angiotensin system in threat processing [3,4] and anxiety [5][6][7]. Although angiotensin II (AT1) receptors are primarily associated with cardiovascular regulation, they are not only expressed in the periphery, but also in brain areas relevant to fear, including amygdala, hippocampus, and prefrontal cortex [8].…”

Stimulating human prefrontal cortex increases reward learning

“…The Information Bias Learning Task (IBLT) is a computerised reinforcement learning paradigm which has been described in detail previously (Browning et al, 2015; Pulcu & Browning, 2017; Pulcu et al, 2019). The IBLT was presented on a laptop computer using Presentation® software (Neurobehavioral Systems, Inc., Berkeley, CA, www.neurobs.com).…”

“…Finally, we hypothesized that tDCS effects would be anatomically specific, with stimulation to prefrontal but not motor cortex (M1) selectively increasing reward learning rates. To measure reward and loss learning rates we used an established reinforcement learning paradigm in which volatility of stimulus-outcome associations is varied across blocks (Browning et al, 2015; Pulcu & Browning, 2017; Pulcu et al, 2019). This task enabled us to test for potential valence- and volatility-specific effects of stimulation.…”