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Randomized Controlled Trial
. 2013 Jun 25;110(26):E2428-36.
doi: 10.1073/pnas.1303061110. Epub 2013 Jun 10.

Single Dose of L-dopa Makes Extinction Memories Context-Independent and Prevents the Return of Fear

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Free PMC article
Randomized Controlled Trial

Single Dose of L-dopa Makes Extinction Memories Context-Independent and Prevents the Return of Fear

Jan Haaker et al. Proc Natl Acad Sci U S A. .
Free PMC article

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 fear memories but generates competing, fear-inhibitory "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.

Keywords: fear conditioning; psychotherapy; reinstatement; renewal; resilience.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Mouse study 1: Attenuation of spontaneous recovery of contextual fear by l-dopa. Administration of 20 mg/kg l-dopa directly after extinction learning (A) results in a long-term reduction of spontaneous recovery (B), as indexed by the percentage of time spent freezing. Gray fields in A indicate the context (identical on all days). Early extinction, first 4 min; late extinction, last 4 min. The graph shows raw values (means ± SEM). For statistical testing, data from tests 1–3 were normalized by subtraction to late extinction to appropriately quantify return of fear (see Materials and Methods and Fig. S1 and Table S1, where results for doses 5 and 10 mg/kg are also given). *P < 0.05 (two-tailed planned post hoc t tests on normalized data).
Fig. 2.
Fig. 2.
Mouse study 2: Attenuation of reinstatement of contextual fear by l-dopa. Administration of 20 mg/kg l-dopa directly after extinction learning (A) results in a reduction of reinstatement 40 d later (Reinst., Test 3) (B). Gray fields in A indicate the context (identical on all days). Lightning bolt denotes UCS. The graph shows raw values (means ± SEM). For statistical testing, data from tests 1 and 2 were normalized by subtraction to late extinction (to quantify spontaneous recovery), and data from test 3 were normalized to data from test 2 (to quantify reinstatement) (see Fig. S2 and Table S2, where results for doses 5 and 10 mg/kg are also given). *P < 0.05 (two-tailed planned post hoc t tests on normalized data).
Fig. 3.
Fig. 3.
Mouse study 3: Attenuation of spontaneous recovery and renewal of cued fear by l-dopa. (A and B) Administration of 20 mg/kg l-dopa directly after extinction learning (A) results in a reduction of spontaneous recovery (Spont. rec., tests 1 and 2, in extinction context B; light gray shading) and ABA renewal (test 3, in the conditioning context A; dark gray shading) (B). The graph shows raw values (means ± SEM). For statistical testing, data from tests 1 and 2 were normalized by subtraction to late extinction (to quantify spontaneous recovery), and data from test 3 were normalized to data from test 2 (to quantify renewal) (Fig. S3 and Table S3). (C) l-dopa also enhances neural activity during test 3 [expression of the immediate early gene (IEG) c-Fos quantified as the number of c-Fos–positive cells per 0.01 mm2] in the vmPFC (infralimbic part) and reduces neural activity in the centromedial amygdala (CeM). (D) Representative stainings. SAL, saline group; opt, optical tract. (Scale bars: 100 μm.) (*)P < 0.1; *P < 0.05; **P < 0.01 (two-tailed planned post hoc t tests on normalized data).
Fig. 4.
Fig. 4.
Human study: Attenuation of renewal of cued fear by l-dopa. (A) Larger differential CRs (CS+ > CS−) in the conditioning context A (dark gray shading; test 2) than in the extinction context B (light gray shading; test 1) on day 2 signify renewal [cue by context interaction (CS+ > CS−)A > (CS+ > CS−)B]. CS presentation in context B effectively assesses spontaneous recovery (test 1). (B) SCR data. Administration of 150 mg of l-dopa directly after extinction learning on day 1 abolishes renewal (test 2). The elimination of renewal is cue-specific (CS+ > CS−). As in the mouse studies, the values shown in the graph (means ± SEM) are not normalized to the preceding experimental phase. Unlike in the mouse studies, statistical analysis was also performed on nonnormalized data, to stay analogous to the fMRI data analysis (Materials and Methods). *P < 0.05 (two-tailed planned post hoc t tests on normalized data). (C) l-dopa also reverses the renewal-related deactivation [cue by context contrast (CS+ > CS−)A < (CS+ > CS−)B; see group-wise contrast estimate bars in Inset] of the vmPFC, resulting in a significant group difference (cue by context by group interaction: Montreal Neurological Institute (MNI) coordinates x, y, z: −10, 44, −20; Z = 3.9; P = 0.013; small volume correction; SVC). For separate CS+ and CS− data, see Table S5. (D) vmPFC peak activation parameter estimates during the renewal test are strongly negatively correlated to corresponding amygdala estimates in l-dopa participants (−20, −2, −12; Z = 3.25; P = 0.034 SVC; R = −0.69). (E) Extracted parameter estimates for CS+ responses in context A from this voxel in l-dopa participants correlate positively with SCRs. fMRI display threshold: P < 0.01; uncorrected. Activation superimposed on an average structural image. L, left.
Fig. 5.
Fig. 5.
Human study: Dopaminergic midbrain to vmPFC resting-state coupling during consolidation. (A) Spontaneous resting-state activity was measured 45 min after extinction and drug administration on day 1 (compare Fig. 4). vmPFC correlation with dopaminergic–midbrain seed region (−6, 40, −18; Z = 3.51; P = 0.043 SVC; R = 0.51; and −4, 36, −18; Z = 3.47; P = 0.048 SVC). Inset shows parameter estimates. (B) Prediction of renewal-related vmPFC activity on day 2 by midbrain–vmPFC resting-state coupling during consolidation on day 1 in l-dopa participants.

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