Evaluation of an Angiotensin Type 1 Receptor Blocker on the Reconsolidation of Fear Memory

Swiercz, Adam; Iyer, Laxmi; Yu, Zhe; Edwards, Alicia B.; Prashant, N M; Nguyen, Bryan; Horvath, Anélia; Marvar, Paul J.

doi:10.1016/j.biopsych.2020.02.453

Cited by 7 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 (an approved treatment for hypertension) can modulate reward and threat processing as well as learning and memory in the absence of negative side effects (Marvar et al, 2014; Reinecke et al, 2018; Pulcu et al, 2019; Zhou et al, 2019a; Swiercz et al, 2020). 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 (Chai et al, 2000) and functionally significant angiotensin II receptors located presynaptically on dopaminergic neurons (Medelsohn et al, 1993; Brown et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Zeng

et al. 2021

Preprint

View full text Add to dashboard Cite

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that modulating interactions between the dopamine and renin-angiotensin system with the angiotensin receptor antagonist Losartan (LT) can modulate learning and reward-related processes. We have therefore determined the behavioral and neural effects of LT on social reward and punishment processing in humans. A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of LT (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation, connectivity and social feedback prediction errors were modelled. Relative to placebo, LT switched reaction times and arousal away from prioritizing punishment towards social reward. On the neural level the LT-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation and attenuated activity in the ventral tegmental area (VTA) and associated connectivity with the bilateral insula in response to punishment during the outcome phase. Computational modelling further revealed an LT-enhanced social reward prediction error signal in VTA and dorsal striatum. LT shifted motivational and emotional salience away from social punishment towards social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Zhou

Zeng

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Based on accumulating evidence from animal and human studies suggesting a role of the AT1R system in regulating fear-and threat-related processes (13,18,(39)(40)(41), we hypothesized that LT would reduce neural vigilance towards fearful oddballs as reflected by attenuated neural reactivity and connectivity in the fronto-limbic fear circuitry. Based on recent evidence suggesting that ATR1 blockade specifically modulates processing of threat-related -but not neutral or salient positive -stimuli (18,19,42), we expected that the neurofunctional decoding analyses would reveal specific effect of LT on the neural expression of subjective fear but not associated affective processes or neural reactivity towards novel oddballs.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zhao

et al. 2022

Preprint

View full text Add to dashboard Cite

There has been growing interest in using pharmacological fMRI to identify novel treatments for fear, yet these models 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. Combining a selective angiotensin II type 1 receptor (ATR1) antagonist with a fear vigilance fMRI paradigm and neurofunctional decoding in n = 87 individuals we demonstrate that AT1R 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, and further show that the observed effect is due to reduced subjective fear, but not threat or non-specific negative affect, using a decoding analysis. Our findings demonstrate a highly specific role of AT1R in subjective fear experience and demonstrate the feasibility of a precision approach to the affective characterization of novel receptor targets for fear in humans.

show abstract

“…Using a rodent model, our laboratory has begun to evaluate integrated cardioautonomic and behavioral measures (Swiercz et al, 2020); building upon the pioneering work of Joseph Ledoux, Oliver Stiedl, and others, (Burhans et al, 2010;LeDoux et al, 1988;Schreurs et al, 2005;Stiedl et al, 2009;Stiedl & Spiess, 1997) demonstrating that heart rate, (Tovote et al, 2005) heart rate (HR) variability, (Stiedl et al, 2009) and blood pressure (Hsu et al, 2012) are reliable indicators of fear memory acquisition that can be used to distinguish between nonspecific and associative threat responses. For example, using an adapted conditioned cardiovascular testing paradigm, we recently showed that recall of a consolidated extinction memory reduces the conditioned cardiovascular response, which is influenced by contextdependent differences in blood pressure and HR sensitivity (Swiercz et al, 2018).…”

Section: Introduction Introductionmentioning

confidence: 99%

“…For example, using an adapted conditioned cardiovascular testing paradigm, we recently showed that recall of a consolidated extinction memory reduces the conditioned cardiovascular response, which is influenced by contextdependent differences in blood pressure and HR sensitivity (Swiercz et al, 2018). Subsequent studies from our laboratory used the same conditioned cardiovascular testing paradigm to evaluate the role of an angiotensin receptor blocker, losartan, on conditioned cardiovascular threat responses independent of extinction learning (Swiercz et al, 2020). These studies provide an example of how using other physiological measures of inhibitory learning (conditioned cardiovascular responses) may help with quantifying the efficacy of extinctionbased interventions and their physiological effects.…”

Section: Introduction Introductionmentioning

confidence: 99%

Internal State-Dependent Conditioned Stimulus Delivery Using Cardiovascular Telemetry in Mice

2021

GWUR

View full text Add to dashboard Cite

To further understand mechanisms of neuropsychiatric disease(s) and their impact on physiological systems, improved pre-clinical models and innovative methodology are needed to assess the internal physiological state of the animal in real-time. To address this challenge we developed a customizable software-based program for Ponemah™ that takes into account the animal's diurnal and resting cardiovascular state in a home-cage environment. Using an integrated Pavlovian fear conditioning and cardiovascular telemetry approach in mice, we demonstrate for the first time a novel software application that can remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the animal's instantaneous cardiovascular state while in its home-cage environment. This new cardiovascular behavioral tool using cardiovascular telemetry extends the ability to quantify integrated physiological correlates of learned fear and may aid in further understanding mechanisms related to enhanced cardiovascular and autonomic arousal in fear and anxietybased disorders.

show abstract

Evaluation of an Angiotensin Type 1 Receptor Blocker on the Reconsolidation of Fear Memory

Cited by 7 publications

References 0 publications

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

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

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

Internal State-Dependent Conditioned Stimulus Delivery Using Cardiovascular Telemetry in Mice

Contact Info

Product

Resources

About