L-DOPA modulates activity in the vmPFC, nucleus accumbens, and VTA during threat extinction learning in humans

TY - JOUR

T1 - L-DOPA modulates activity in the vmPFC, nucleus accumbens, and VTA during threat extinction learning in humans

AU - Esser, Roland

AU - Korn, Christoph W

AU - Ganzer, Florian

AU - Haaker, Jan

N1 - © 2021, Esser et al.

PY - 2021/9/2

Y1 - 2021/9/2

N2 - Learning to be safe is central for adaptive behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and an essential process for the behavioural treatment of anxiety-related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes the absence of an expected threat. Here we show that such a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement via administration of L-DOPA (vs. Placebo) was associated with reduced retention of differential psychophysiological threat responses at later test, which was mediated by activity in the ventromedial prefrontal cortex that was specific to extinction learning. L-DOPA administration enhanced signals at the time-point of an expected, but omitted threat in extinction learning within the nucleus accumbens, which were functionally coupled with the ventral tegmental area and the amygdala. Computational modelling of threat expectancies further revealed prediction error encoding in nucleus accumbens that was reduced when L-DOPA was administered. Our results thereby provide evidence that extinction learning is influenced by L-DOPA and provide a mechanistic perspective to augment extinction learning by dopaminergic enhancement in humans.

AB - Learning to be safe is central for adaptive behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and an essential process for the behavioural treatment of anxiety-related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes the absence of an expected threat. Here we show that such a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement via administration of L-DOPA (vs. Placebo) was associated with reduced retention of differential psychophysiological threat responses at later test, which was mediated by activity in the ventromedial prefrontal cortex that was specific to extinction learning. L-DOPA administration enhanced signals at the time-point of an expected, but omitted threat in extinction learning within the nucleus accumbens, which were functionally coupled with the ventral tegmental area and the amygdala. Computational modelling of threat expectancies further revealed prediction error encoding in nucleus accumbens that was reduced when L-DOPA was administered. Our results thereby provide evidence that extinction learning is influenced by L-DOPA and provide a mechanistic perspective to augment extinction learning by dopaminergic enhancement in humans.

KW - Adult

KW - Brain/drug effects

KW - Extinction, Psychological/drug effects

KW - Fear/drug effects

KW - Humans

KW - Levodopa/pharmacology

KW - Male

KW - Nucleus Accumbens/drug effects

KW - Prefrontal Cortex/drug effects

KW - Ventral Tegmental Area/drug effects

KW - Young Adult

U2 - 10.7554/eLife.65280

DO - 10.7554/eLife.65280

M3 - SCORING: Journal article

C2 - 34473055

VL - 10

JO - ELIFE

JF - ELIFE

SN - 2050-084X

M1 - e65280

ER -