Abstract
Extinction is considered a core mechanism underlying exposure-based therapy in anxiety-related disorders. However, marked impairments in threat extinction learning coupled with impaired neuroplasticity in patients strongly impede the efficacy of exposure-based interventions. Recent translational research suggests a role of the renin-angiotensin (RA) system in both these processes. However, the efficacy of pharmacological modulation of the RA system to enhance threat extinction in humans and the underlying neural mechanisms remain unclear. The present pre-registered, randomized placebo-controlled pharmacological neuroimaging trial demonstrates that pre-extinction administration of the angiotensin II type 1 receptor antagonist losartan accelerated attenuation of the psychophysiological threat response during extinction. On the neural level the acceleration of extinction was accompanied by threat-signal specific enhanced ventromedial prefrontal cortex (vmPFC) activation and its coupling with the basolateral amygdala. Multivoxel pattern analysis and voxel-wise mediation analysis further revealed that that losartan reduced the neural threat expression, particularly in the vmPFC, and confirmed that acceleration of extinction critically involved treatment-induced modulation of vmPFC activation. Overall the results provide the first evidence for a pivotal role of the RA system in extinction learning in humans and suggest that adjunct losartan administration can be leveraged to facilitate the efficacy of extinction-based therapies.
