Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala

Abstract

Recent translational research suggests a role of the renin-angiotensin (RA) system in threat extinction and underlying neuroplasticity; however, whether and how pharmacological modulation of the RA system influences physiological and neural manifestations of threat during extinction learning in humans is unclear. Here we report that pre-extinction administration of losartan, an angiotensin II type 1 receptor antagonist, accelerated attenuation of physiological threat expression. During early extinction, losartan enhanced threat-signal specific ventromedial prefrontal cortex (vmPFC) activation and its coupling with the basolateral amygdala. Multivoxel pattern analysis revealed that losartan reduced whole brain, particularly vmPFC, threat expression and voxel-wise mediation analyses further confirmed that losartanaccelerated extinction crucially involved vmPFC processing. Overall the results provide initial evidence for a critical role of the RA system in extinction learning in humans and suggest that adjunct losartan administration may facilitate the efficacy of extinction-based therapies.RCT Identifier: NCT03396523 (ClinicalTrials.gov)

The angiotensin antagonist Losartan modulates social reward motivation and punishment sensitivity via modulating midbrain-striato-frontal circuits

“…On the behavioral level LT shifted the motivational significance and arousal experience for social punishment relative to social reward feedback, an effect that was mainly driven by prolonged reaction times during anticipation of and subsequently reduced arousal reaction towards social punishment stimuli. These findings partly align with observations in previous studies, such that following LT healthy subjects perceived loss outcomes as being less informative resulting in an attenuated loss learning rate (29), and exhibited accelerated extinction and autonomous arousal decreases towards threat (26). Together, these observations indicate that LT may attenuate the impact of negative information thus shifting anticipatory motivation and post encounter learning towards positive information.…”

“…Social deficits such as decreased social motivation or a hypersensitivity to social punishment represent a core symptom across several mental disoders including depression (2, 3), social anxiety disorder (4), post-traumatic stress disorder (5,15), autism spectrum disorder (7, 8), and schizophrenia (9). Together with accumulating evidence from previous studies (26,27,29) our findings suggest that LT may have a promising potential to enhance social motivation to obtain rewards while decreasing sensitivity to punishment in social contexts and attenuate these dysregulations in patient populations.…”

“…To reduce potential confounding effects of early life stress (46), impulsiveness, sensitivity to punishment and reward on reward-related neural processing the Childhood Trauma Questionnaire (CTQ), Barratt Impulsiveness Scale (BIS), and Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ) were administered at baseline (Figure 1A) (47)(48)(49). Given that after oral administration LT peak plasma levels are reached after 90 minutes with a terminal elimination half-life ranging from 1.5 to 2.5 hours (50-52) the experimental paradigm started 90 minutes after treatment (in line with (26,53)). LT rapidly crosses the blood-brain barrier (54,55) and while effects at central receptors have been observed after 30 minutes after i.e.…”

“…administration effects on cardiovascular indices only become apparent after 3 hours (e.g. (50) , see also (26,29)). To further control for potential confounding effects of LT on cardiovascular activity blood pressure and heart rate were assessed before drug administration, as well as before and after the fMRI paradigm (Figure 1A).…”

“…Recent pharmacological studies in healthy humans have demonstrated that targeting the renin-angiotensin system (RAS) via the angiotensin II type 1 receptor (AT1R) antagonist losartan (LT, an approved treatment for hypertension) can modulate reward and threat processing as well as learning and memory in the absence of negative side effects (25)(26)(27)(28)(29). Earlier animal models suggest an interaction between the RAS and the central DA system, including a dense expression of RAS receptors in midbrain-striato-prefrontal circuits (30) and functionally significant angiotensin II receptors located presynaptically on dopaminergic neurons (31,32).…”