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.