Dopaminergic drugs modulate fear extinction related processes in humans, but effects are mild

Abstract

The ability to extinguish learned fear responses is crucial for adaptive behavior. The mesolimbic dopaminergic system originating in the ventral tegmental area has been proposed to contribute to fear extinction learning because of its critical role in reward learning. The unexpected omission of aversive unconditioned stimuli (US) is considered as rewarding (outcome better than expected) and to drive extinction learning. We tested the hypothesis that extinction learning is facilitated by dopaminergic drugs and impeded by anti-dopaminergic drugs. The effects of dopamine agonists [levodopa (100 mg) and bromocriptine (1.25 mg)] and antagonists [tiapride (100 mg) and haloperidol (3 mg)] on fear extinction learning were compared to placebo in 146 young and healthy human participants. A three-day differential fear conditioning paradigm was performed with pupil size and skin conductance responses (SCRs) being recorded. Fear acquisition training was performed on day 1, extinction training on day 2, and recall was tested on day 3. The conditioned stimuli (CS+, CS-) consisted of two geometric figures. A short electrical stimulation was used as the aversive US. One of the four drugs or placebo was administered prior to the extinction phase on day 2. Overall, effects were small and seen only in the bromocriptine group. In line with our hypothesis, we measured reduced pupil dilation during late recall in the bromocriptine group compared to the placebo group, indicating faster re-extinction of spontaneously recovered fear reactions on the third day. Effects of levodopa and haloperidol were unspecific and related to generally increased SCR levels in the levodopa group (already prior to drug intake), and miotic side-effects of haloperidol. Findings provide additional support that the dopaminergic system contributes to extinction learning in humans, possibly by improving consolidation of fear extinction memory.