Effects of post-extinction l-DOPA administration on the spontaneous recovery and reinstatement of fear in a human fMRI study

Relapse is a pertinent problem in the treatment of anxiety disorders. In the laboratory, relapse is modeled as return of conditioned fear responses after successful fear extinction and is explained by insufficient retrieval and/or expression of the fear-inhibitory extinction memory that is generated during extinction learning. We have shown in mice and humans that return of fear can be prevented by administration of a single dose of the dopamine precursor l-3,4-dihydroxyphenylalanine (l-DOPA) immediately after extinction. In mice, this effect could be attributed to an enhancement of extinction memory consolidation. In our human study, we could not exclude that l-DOPA might have acted by interfering with the consolidation of the original fear memory. In the present study, we therefore used a combined differential cue and context conditioning paradigm where initial fear conditioning and extinction were conducted one day apart, in analogy to previous mouse studies. l-DOPA (N=21) or placebo (N=19) were administered after extinction, precluding any action on fear memory consolidation. In the return-of-fear test conducted one week later, drug effects on conditioned skin conductance responses were absent. However, we found evidence indicative of reduced neural activity, measured with functional magnetic resonance imaging (fMRI), in the l-DOPA group in areas related to conditioned fear and return of fear (amygdala, posterior hippocampus) and enhanced activity in a key area of extinction retrieval/expression (ventromedial prefrontal cortex), relative to placebo controls. These findings require further corroboration in additional experiments. Implications for further investigations on the role of the dopamine system in extinction and on the neuropharmacological augmentation of extinction-based therapies are discussed.