Angiotensin II regulates the neural expression of subjective fear in humans - precision pharmaco-neuroimaging approach

Abstract

BackgroundRodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear. MethodsIn a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined. ResultsAT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (1) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (2) does not affect reactivity to novel oddballs. ConclusionsThese results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.