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

  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker  Is a corresponding author
  1. Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany
  2. Section Social Neuroscience, Department of General Psychiatry, Germany
  3. German Center for Addiction Research in Childhood and Adolescence, University Medical Center Hamburg-Eppendorf, Germany
Research Article
Cite this article as: eLife 2021;10:e65280 doi: 10.7554/eLife.65280
5 figures and 2 additional files

Figures

Behavioural and psychophysiological outcome measures on days 1, 2, and 3.

(a) US expectancy, (b) SCR, and (c) fear ratings reflect successful acquisition of CS–US contingencies during acquisition and decreasing responses during extinction training.Retention of CS-US memory was evident during retention test on day 3, as well as initialenhancement of responses after reinstatement within three trials after presentation of thereinstatement USs. Differential SCRs (CS+ − CS−) in three trials after reinstatement were lowerin the L-DOPA, when compared to the Placebo group (see Figure 2). SCR = skin conductanceresponses, CS = conditioned stimulus.

Figure 2 with 2 supplements
L-DOPA administration during extinction learning decreased differential SCRs after reinstatement on day 3.

Differential SCRs (CS+ > CS−) were decreased when compared to the Placebo group within three trials after the reinstatement procedure (ANOVA: CS-type by group interaction). See Figure 2—figure supplement 1l for CS-specific and trial-wise responses. Additional analyses that include two to five trials revealed a difference between groups in differential SCRs (see Supplementary file 1 and Figure 2—figure supplement 2). SCR = skin conductance responses, CS = conditioned stimulus.

Figure 2—figure supplement 1
L-DOPA administration during extinction learning decreases SCRs after reinstatement.

(a) Mean CS-specific responses across three trials. (b) Trial-wise responses to the CS+ in both groups three trials before and after reinstatement. (c) Trial-wise responses to the CS+ in both groups three trials before and after reinstatement. Asterisk indicate a p-value<0.05 for a CS-type by group interaction. See main text Figure 2 for illustration of differential responses.

Figure 2—figure supplement 2
Effect sizes for comparisons of differential CS responses between groups (one-sided unpaired t-test) before and after reinstatement.
L-DOPA augmented vmPFC activity during extinction learning (day 2) that mediated retrieval of threat responses (day 3).

(a) VmPFC responses that reflected CS+ trials during extinction training when subjects no longer expected an US that are contrasted with trials in which an US was expected (i.e., extinction learning). One-sided independent t-test L-DOPA > Placebo, MNI xyz: 10, 35,–7; Z = 4.76; pFWE-SVC=0.002; displayed at threshold punc<0.005; colour bar represents t-values. Estimates in the vmPFC were enhanced after administration of L-DOPA as compared to placebo (a.u. = arbitrary units; error-bar indicate the standard error of the mean). (b) Higher individual vmPFC responses across groups that reflected decreasing US expectancy for the CS+ (i.e., extinction learning) were associated with lower conditioned responses (SCR CS+ > CS−) during retrieval test 24 hr later (two-sided Pearson correlation). (c) The effect of L-DOPA treatment on conditioned responses (SCR CS+ > CS−) during retrieval test was fully mediated via the activity of the vmPFC in extinction learning. Drug treatment (L-DOPA vs. Placebo) had an effect on vmPFC activity (β = −2.2957, standard error = 0.4227, t(38)=-5.431, p=0.000003), and vmPFC activity had a negative effect on conditioned responses during retrieval test (β = −0.01898, standard error = 0.008888, t(38) = –2.135, p=0.0392). We found no evidence for an effect of drug treatment (L-DOPA vs. Placebo) on conditioned responses during retrieval test (β = 0.02644, standard error = 0.03238, t(38) = 0.816, p=0.419), but when including vmPFC activity into that model, this mediator was significant (β = −0.02478, standard error = 0.01192, t(38) = –2.079, p=0.0446; effect of group p=0.4). There was further evidence for a full mediation of drug treatment (L-DOPA vs. Placebo) on conditioned responses by an indirect effect of vmPFC activity within a mediation model using quasi-bayesian procedures (β = 0.0563, 95% confidence intervals = 0.007–0.12, p=0.038, N = 40,1000 samples, N = 40); bootstrapping yielded comparable results (β = 0.056, 95% confidence intervals = 0.007–0.14, p=0.044). a.u. = arbitrary units, vmPFC = ventromedial prefrontalcortex, CS = conditioned stimulus, US = unconditioned stimulus, SCR = skin conductance responses.

Figure 4 with 1 supplement
Omission of expected aversive outcomes in the NAcc is modulated by L-DOPA during extinction training on day 2.

(a) At the time-point of US omission, the Placebo group exhibited expectancy violation coding (fitted prediction error term) in the right NAcc, which was not observed in participants that received L-DOPA (one-sided independent t-test Placebo > L-DOPA, MNI xyz: 9, 18,–4; Z = 3.02; pFWE-SVC=0.043). (b) Administration of L-DOPA abolished negative categorial responses (i.e., independent of expectancy) to omitted USs in the left NAcc that were found in Placebo controls (one-sided independent t-test L-DOPA > placebo, MNI xyz: –11, 14, –10; Z = 3.22; pFWE-SVC=0.029). Neural correlates are displayed at threshold punc<0.005 with bar plot showing parameter estimates (a.u.). We found no group differences in functional connectivity during CS+ presentations in extinction training or acquisition training, as well as no differences during US presentations during acquisition training (see table Supplementary file 1o). a.u. = arbitrary units, NAcc = nucleus accumbens, US = unconditioned stimulus.

Figure 4—figure supplement 1
Enhanced associability related neural signalling in the left amygdala after the administration of L-DOPA.

Modelled associability (i.e., attention shift to the omitted US) during the omitted US was related to stronger activation of the left amygdala (MNI xyz: −21, –6, –23; Z = 3.86; pFWE-SVC=0.013; displayed at threshold punc<0.005 with bar plot showing parameter estimates [a.u.]) after administration of L-DOPA when compared with placebo controls.

Dopaminergic modulation of functional connectivity between the nucleus accumbens and the VTA at the time-point of US omission during extinction training on day 2.

(a) Administration of the dopaminergic precursor L-DOPA enhanced connectivity between the bilateral nucleus accumbens (seed, see left) and the left amygdala (one-sided comparison L-DOPA > placebo, MNI xzy: 24, –11, –10; Z = 3.73; p(FWE)=0.024), when compared to the Placebo group (contrast L-DOPA > Placebo). (b) Dopaminergic enhancement was furthermore associated with strengthened connectivity of the substantia nigra/ventral tegmental area complex and nucleus accumbens (one-sided comparison, L-DOPA = 1, Placebo = 0: MNI xzy: −8, –16,–15; Z = 3.43; p(FWE)=0.039). This contrast is specific to the enhancement of connectivity by L-DOPA, while making no assumptions about the Placebo group. The connectivity was condition-specific to the time-point of US omission (psycho-physiological interaction, PPI in SPM). We found functional connectivity during CS+ presentations in extinction training or acquisition training, as well as no differences during US presentations during acquisition training between these regions, as well as no differences between groups during CS+ presentations in extinction training (see Supplementary file 1o). T-maps are displayed at threshold punc<0.005; colour bar represents t-values. a.u. = arbitrary units, NAcc = nucleus accumbens, SN/VTA = substantia nigra/ventral tegmental area complex.

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