Introduction
Adaptive processing of social feedback is vital for interpersonal functioning and mental health. Dysregulations in this domain and its underlying neural processes contribute to the development and maintenance of major psychiatric disoders including depression (1-3), social anxiety disorder (SAD) (4), post-traumatic stress disorder (PTSD) (5), addiction (6), autism spectrum disorder (ASD) (7, 8), and schizophrenia (9). While these disorders cause tremendous individual suffering and socio-economic costs the development of novel treatments that target social deficits based on the underlying neurobiological dysregulations remains challenging (10, 11).
The Research Domain Criteria (RDoC) framework aims to facilitate novel treatment development by conceptualizing psychiatric disorders from basic dimensions of functioning, including the domains of social communication as well as reward/loss evaluation (12). Together these domains may represent a transdiagnostic treatment target with the potential to improve social functioning. Dysregulations in midbrain-striato-prefrontal circuits have been increasingly established as a core pathogenic mechanism across psychiatric disorders (3, 13-16). Findings from human imaging studies suggest that this circuitry overlaps with that involved in social reward and punishment processing (17, 18) and animal models indicate that neurochemical signalling in this circuitry critically regulates social reward and punishment (19-21). Dopamine (DA) and its interactions with other neurotransmitter systems such as oxytocin play an important role in modulating social reward and punishment in these cicruits (5, 22), however, direct pharmacological modulation of these systems commonly results in negative side effects or highly context-dependent effects, respectively, which critically impede the clinical utility of these approaches (11, 23, 24).
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 (LT, an approved treatment for hypertension) can modulate reward and threat processing as well as learning and memory in the absence of negative side effects (25-29). 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 (30) and functionally significant angiotensin II receptors located presynaptically on dopaminergic neurons (31, 32). LT induced concentration-dependent inhibition of dopamine release via inactivation of AT1R (33), but also enhanced dopamine D1 receptor (D1R) signaling which may contribute to both its effects on hypertension (34) and reward-related processes (35, 36). Additionally, optogenetic inhibition/activation of ventral tegmental area (VTA) dopaminergic neurons, which exhibit dense AT1R expression, revealed that cue-evoked DA release accurately encodes reward prediction errors (37, 38), thus supporting behavioral adaptation and associative learning (39, 40). Together, the available evidence suggests that targeting the RAS via LT may represent a promising candidate to modulate neural processing in midbrain-striatal-prefrontal circuits which critically mediate flexible behavioral adaption in the domains of feedback-dependent learning as well as earlier stages of social and non-social reward processing (17, 18, 22, 41, 42). Initial evidence for the functional and behavioral relevance of this strategy in humans comes from a recent study that demonstrated that a single dose of 50mg LT can modulate feedback-dependent learning in healthy individuals such that LT enhanced the difference between loss and reward feedback learning rates and suppressed loss learning rates (29). Determining behavioral and neural effects on earlier stages of reward and punishment processing in social contexts will facilitate a translational neuroimaging approach which facilitates both translation from animal models, indicating that RAS-DA interactions modulate reward-related processing in these cicruits (19, 20, 35, 36), and translation into therapeutic application in populations with social deficits.
Reward-related neural responses in this circuitry encompass anticipatory and consummatory signals, closely linked to brain activation in the midbrain-striatal-frontal circuit, particularly the VTA, striatum, and frontal cortex (17, 18, 22). From a computational modelling framework, prediction error (PE) signals critically rely on DA-dependent signaling in these areas (43), although the prediction error is not limited to reward and punishment processing but also includes sensory-perceptual processes as well as higher order processes such as social learning (43-45).
Against this background we combined a pre-registered randomized double-blind between-group placebo-controlled pharmacological experiment with functional MRI (fMRI) and computational modelling to examine whether social reward and punishment processing can be modulated by a single dose of LT, thus bridging the translational gap between animal model and human research as well as to determine the clinical potential of LT. To this end healthy volunteers (n=87) underwent a well-validated social incentive delay (SID) fMRI paradigm (5). Behavioral indices reflecting motivation and subsequent emotional impact of social feedback, neural indices during reward and punishment anticipation and outcome, as well as social feedback PE signalling served as primary outcomes. Based on findings from animal and human studies we hypothesized that LT would (a) enhance differential processing of reward and punishment on the behavioral level (29), which on the neural level would be reflected in (b) enhanced differential activiation and connectivity in VTA-striatal-frontal circuits during social reward-punishment processing, and (c) enhance social feedback PE signalling during the outcome phase.