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Research Articles, Behavioral/Cognitive

The Angiotensin Antagonist Losartan Modulates Social Reward Motivation and Punishment Sensitivity via Modulating Midbrain-Striato-Frontal Circuits

Xinqi Zhou, Ting Xu, Yixu Zeng, Ran Zhang, Ziyu Qi, Weihua Zhao, Keith M. Kendrick and Benjamin Becker
Journal of Neuroscience 18 January 2023, 43 (3) 472-483; DOI: https://doi.org/10.1523/JNEUROSCI.1114-22.2022
Xinqi Zhou
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
2Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, 610066, China
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Ting Xu
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Yixu Zeng
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Ran Zhang
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Ziyu Qi
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Weihua Zhao
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Keith M. Kendrick
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Benjamin Becker
1The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
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Abstract

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine (DA) and renin-angiotensin system (RAS) may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the Angiotensin II type 1 receptor (AT1R) antagonist losartan on social reward and punishment processing in humans. A preregistered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay (SID) functional MRI (fMRI) paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of losartan (50 mg, n = 43, female = 17) or placebo (n = 44, female = 20). We evaluated reaction times (RTs) and emotional ratings as behavioral and activation and functional connectivity as neural outcomes. Relative to placebo, losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Thus, losartan modulated approach-avoidance motivation and emotional salience during social punishment versus 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.

SIGNIFICANCE STATEMENT Social deficits and anhedonia characterize several mental disorders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the Angiotensin II type 1 receptor (AT1R) via losartan with functional MRI (fMRI) to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disorders.

  • dopamine
  • losartan
  • social reward
  • striatum
  • ventral tegmental area

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The Journal of Neuroscience: 43 (3)
Journal of Neuroscience
Vol. 43, Issue 3
18 Jan 2023
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The Angiotensin Antagonist Losartan Modulates Social Reward Motivation and Punishment Sensitivity via Modulating Midbrain-Striato-Frontal Circuits
Xinqi Zhou, Ting Xu, Yixu Zeng, Ran Zhang, Ziyu Qi, Weihua Zhao, Keith M. Kendrick, Benjamin Becker
Journal of Neuroscience 18 January 2023, 43 (3) 472-483; DOI: 10.1523/JNEUROSCI.1114-22.2022

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The Angiotensin Antagonist Losartan Modulates Social Reward Motivation and Punishment Sensitivity via Modulating Midbrain-Striato-Frontal Circuits
Xinqi Zhou, Ting Xu, Yixu Zeng, Ran Zhang, Ziyu Qi, Weihua Zhao, Keith M. Kendrick, Benjamin Becker
Journal of Neuroscience 18 January 2023, 43 (3) 472-483; DOI: 10.1523/JNEUROSCI.1114-22.2022
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Keywords

  • dopamine
  • losartan
  • social reward
  • striatum
  • ventral tegmental area

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