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Randomized Controlled Trial
. 2019 Dec;236(12):3401-3412.
doi: 10.1007/s00213-019-05301-4. Epub 2019 Jun 26.

L-DOPA Improves Extinction Memory Retrieval After Successful Fear Extinction

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Free PMC article
Randomized Controlled Trial

L-DOPA Improves Extinction Memory Retrieval After Successful Fear Extinction

A M V Gerlicher et al. Psychopharmacology (Berl). .
Free PMC article

Abstract

Rationale: A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction.

Methods: In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session.

Results: In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction.

Conclusion: The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session.

Keywords: Anxiety; Cognitive-behavioural therapy; Dopamine; Exposure treatment; Extinction; Fear conditioning; Memory consolidation; Post-traumatic stress disorder.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Experimental design of experiment 1 and 2. a In order to test the potential influence of inter-individual differences in extinction success on the effect of a post-extinction administration of L-DOPA on extinction memory retrieval, we aimed to increase inter-individual variability in extinction success by reducing the number of trials during extinction compared to a previous study (Gerlicher et al. 2018) from 15 to 10 CS+ and CS- trials in experiment 1. b In experiment 2, we aimed to induce successful extinction learning experimentally by increasing the number of trials during the extinction session from 15 in a previous study (Gerlicher et al. 2018) to 25 CS+ and CS- trials (long extinction) in experiment 2
Fig. 2
Fig. 2
Trial by trial SCRs to CS+ and CS- during conditioning on day 1, extinction on day 2 and test on day 3. Skin conductance responses of a placebo (N = 35) and b L-DOPA-treated (N = 35) participants in experiment 1 did not differ significantly in any of the experimental phases. In contrast to previous findings (Gerlicher et al. 2018), there was no of effect of L-DOPA administration after short extinction on group average CS+ compared to CS- SCRs during test on day 3. Similarly, in experiment 2 groups treated with c placebo (N = 14) and d L-DOPA (N = 16) after a long extinction session did also not differ significantly in any of the experimental phases. Note, however, that the intended manipulation of prolonging extinction in order to fully reduce CRs was not successful and the long extinction session did not result in a complete reduction of differential (CS+ > CS-) SCRs at the end of the extinction session. Error bars depict standard error of the mean. Arrows indicate time point of drug administration
Fig. 3
Fig. 3
Relationship between CRs at the end of extinction on day 2 and CRs during test on day 3 in placebo and L-DOPA-treated participants in experiments 1 (upper panels) and 2 (lower panels). a Whereas there was no significant relationship between CRs (SCR CS+ > CS-) at the end of extinction on day 2 and CRs (SCR CS+ > CS-) at test on day 3 in placebo-treated participants (N = 35), b there was a significant positive relationship after post-extinction L-DOPA administration (N = 35) in experiment 1. c Post hoc comparison of L-DOPA (N = 16) compared to placebo-treated individuals (N = 12) with a complete reduction of CRs ((SCR CS+ > CS-) ≤ 0, ‘low CR’ in the panel) revealed that L-DOPA significantly improved extinction memory retrieval after successful within-session extinction. In contrast L-DOPA (N = 19) compared to placebo-treated (N = 23) individuals with high CRs ((SCR CS+ > CS-) > 0) at the end of extinction showed a trend towards impaired extinction memory retrieval. d Replicating the effect of experiment 1, also in experiment 2 not placebo (N = 14), but e only L-DOPA-treated participants (N = 16) showed a significant positive relationship between CRs (SCR CS+ > CS-) at the end of extinction on day 2 and CRs (SCR CS+ > CS-) at test at test 24 h later. f Point estimates of CRs (SCR CS+ > CS-) at test for participants with low (mean – 1 SD) and high (mean + 1 SD) CR at the end of extinction show that also in experiment 2, L-DOPA was only beneficial in individuals showing successful within-session extinction, but may have detrimental effects after non-complete within-session extinction. Error bars depict standard error of the mean

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