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

Zhang, Ran; Zhao, Weihua; Qi, Ziyu; Xu, Ting; Zhou, Feng; Becker, Benjamin

doi:10.1101/2022.05.01.490234

Cited by 4 publications

(1 citation statement)

References 73 publications

(125 reference statements)

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“…In line with such clinical effects, we have recently shown that a single dose of the ARB losartan prevents a physiological stress response and facilitates contextual processing during experimental trauma, two processes known to be relevant to the development of posttraumatic stress disorder (PTSD,16). Similarly, administration of losartan has been associated with reductions in subjective fear during a aversive task (17) and encoding of negative memories (18). Identifying specific aspects of learning (e.g., prediction errors or learning rates) impacted by RAS-modulating drugs can help us understand the function they play in the prevention of anxiety development.…”

Section: Main Text Introductionmentioning

confidence: 79%

Reduction of aversive learning rates in Pavlovian conditioning by angiotensin II antagonist losartan: a randomised controlled trial

Zika¹,

Appel²,

Klinge³

et al. 2023

Preprint

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The angiotensin receptor blocker losartan has been linked to aspects of aversive learning such as fear acquisition and extinction, inhibition of aversive learning rates and reduced post-traumatic stress disorder (PTSD) symptoms. Here, we investigate the influence of losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized placebo-controlled design, we tested 45 healthy volunteers during a baseline session (session 1), after application of losartan or placebo (session 2) and during a follow-up session (session 3). On each session, participants engaged in a task where they had to predict the likelihood of an electrical stimulation on every trial while the true shock contingencies repeatedly switched between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. Acute administration of losartan significantly reduced participants’ adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates on the drug session compared to baseline. The 50mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out general reduction in attention and engagement. Decreased adjustment of aversive expectations to low-to-high, but not high-to-low, threat change was maintained on a follow up session 24hrs later, suggesting a possible role of losartan in prevention of formation of aversive associations on longer time scales.

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Section: Main Text Introductionmentioning

confidence: 79%

Reduction of aversive learning rates in Pavlovian conditioning by angiotensin II antagonist losartan: a randomised controlled trial

Zika¹,

Appel²,

Klinge³

et al. 2023

Preprint

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Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial

Zika,

Appel,

Klinge

et al. 2024

Biological Psychiatry

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The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

Chen

Zhou

et al. 2023

Preprint

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The brain renin angiotensin II system plays a pivotal role in cognition and neuropathology via the central angiotensin II type 1 receptor (AT1R), yet the lack of a biologically informed framework currently impedes translational and therapeutic progress. We combined imaging transcriptomic and meta-analyses with pharmaco-resting state fMRI employing a selective AT1R antagonist in a discovery-replication design (n=132 individuals). The AT1R was densely expressed in subcortical systems engaged in reward, motivation, stress, and memory. Pharmacological target engagement suppressed spontaneous neural activity in subcortical systems with high AT1R expression and enhanced functional network integration in cortico-basal ganglia-thalamo-cortical circuits. AT1R-regulation on functional network integration was further mediated by dopaminergic, opioid and corticotrophin-releasing hormone pathways. Overall, this work provides the first comprehensive characterization of the architecture and function of the brain renin angiotensin II system indicating that the central AT1R mediates human cognition and behavior via regulating specific circuits and interacting with classical transmitter systems.

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

Cited by 4 publications

References 73 publications

Reduction of aversive learning rates in Pavlovian conditioning by angiotensin II antagonist losartan: a randomised controlled trial

Reduction of aversive learning rates in Pavlovian conditioning by angiotensin II antagonist losartan: a randomised controlled trial

Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

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