Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear

Abstract

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fearmemories but generates competing, fearinhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression - and, thus, return of fear - is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine- dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.