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

Abstract

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.

Angiotensin blockade enhances motivational reward learning via enhancing striatal prediction error signaling and frontostriatal communication

“…The current pattern of results may reflect modulatory effects of RAS blockade on dopaminergic neurotransmission given that LT has been shown to induce stronger D1 receptor expression (46) which has been associated with better reward-associative learning (47). These findings resonate with recent studies reporting an LT-induced enhancement of learning from positive relative to negative events (12) as well as an LT-induced shift from preferential social punishment towards social reward processing (17). Together, this pattern of effects suggests that LT can attenuate the impact of negative information thus promoting motivation to select rewarding options.…”

“…Seventy right-handed healthy male Chinese participants were screened according to evaluated enrollment criteria (see Supplemental Methods, sample size based on previous studies [15][16][17]). The study focused on male individuals to control for sex differences in response to RAS blockade [22] and menstrual cycle-dependent variations in reward processing [23].…”

“…Effects of LT on learning transfer were examined by comparing choices and functional connectivity in cortico-striatal pathways when participants approached the best or avoided the worst stimulus. Based on previous literature (12, 16, 17), we predicted that LT would: 1) reduce learning from negative outcomes, increase the RPE-associated signaling in the ventral striatum (VS) and its neural expression for positive outcomes during the learning phase and 2) increase selection of the best stimulus in the context of increased fronto-striatal coupling during learning transfer.…”

“…Moreover, LT specifically affected probabilistic learning from negative outcomes by reducing the degree to which participants learned from loss feedback, while leaving learning from positive outcomes unaffected (12). An initial neuroimaging study moreover reported modulatory effects of LT on mesocorticolimbic functional connectivity during social reward and punishment processing (17).…”

Angiotensin antagonist inhibits preferential negative memory encoding via decreasing hippocampus activation and its coupling with amygdala

“…Growing evidence from animal models and human findings have suggested a crucial role of the renin-angiotensin system (RAS) in emotion and memory formation which may overlap with processes relevant for the development of PTSD (15–17). Different lines of research have indicated an important role of the RAS in the development of PTSD such that (1) blood levels of renin were elevated in individuals with trauma-experience (18), (2) treatment with angiotensin blockers, particularly the angiotensin II type 1 receptor antagonist losartan (LT) during trauma exposure reduced the incidence of PTSD (19, 20), and (3) administration of LT in healthy controls also reduced autonomic stress reactivity during experimental trauma induction (21) and shifted emotional reactivity from negative to positive information (22, 23). While these findings support that targeting the RAS via LT may prevent the development of PTSD by modulating emotional or memory formation processes, the underlying behavioral and neurobiological mechanisms have not been examined.…”