Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. In the psychotherapy of fear or anxiety disorders, patients make safety experiences that generate fear-inhibitory safety memories. Fear, however, frequently returns because safety memory retrieval fails. We find that safety memories can be strengthened and are more easily retrieved when adding a standard anti-Parkinson drug that augments brain levels of the neurotransmitter dopamine directly after a safety experience. In mice and humans, this treatment up-regulates an anti-fear area in the frontal cortex. Our findings open a unique avenue for improving psychotherapy.

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.

In extinction, conditioned fear responses (CRs) are diminished by using repeated exposure to the conditioned fear stimulus (CS) in the absence of the aversive unconditioned stimulus (UCS) with which it had previously been paired (1). Most extinction protocols do not, or only partly, delete the original CS–UCS association (or fear memory) but result in the formation of an inhibitory CS–no-UCS association (extinction memory) (2, 3). At later CS exposures (test), the competition between both memory traces is thought to determine the level of conditioned responding. Dissimilarity between the test and the extinction context impairs the retrieval or expression of the extinction memory in favor of the retrieval/expression of the fear memory, which is thought to not require gating or occasion-setting by any particular context (2). In the laboratory, context dissimilarity is achieved by testing in a physically different context than extinction (renewal), by again administering UCSs shortly before testing (reinstatement) or by simply letting sufficient time pass between extinction and testing (spontaneous recovery) (2). The return of fear observed in these situations is considered a laboratory model of relapse after successful extinction-based psychotherapy of conditions such as posttraumatic stress disorder, panic disorder, or social phobia (2, 4, 5).

To generate strong and long-lasting memories, new learning must initiate cascades of molecular events that ultimately result in changes in protein expression and/or posttranslational protein modification (6⇓–8). Animal studies have shown that release of the neurotransmitter dopamine is critically important in many such consolidation processes and specifically promotes stable forms of long-term potentiation, a cellular correlate of long-term memory (9⇓⇓⇓–13). In the domain of extinction, administration of dopamine receptor antagonists before or after extinction consistently impairs animals’ capacity to later express extinction, leading to enhanced CRs at test (i.e., return of fear) (14⇓–16). Conversely, extinction expression is improved in animals that receive the combined dopamine and norepinephrine reuptake blocker methylphenidate directly after extinction (17), suggesting that dopamine contributes to extinction memory consolidation. These findings led us to ask whether administration of the dopamine precursor l-dopa directly after extinction (i.e., during memory consolidation) would enhance extinction memory formation and thereby prevent the return of fear.

Results and Discussion

Translation to Humans. The likely human homolog for the rodent IL can be found in ventromedial aspects of the PFC (29), and studies indicate that human extinction also uses a vmPFC-based circuitry. In particular, results from functional magnetic resonance imaging (fMRI) experiments on fear/extinction memory expression are consistent with a vmPFC–amygdala interaction (e.g., refs. 30⇓–32). In our human study, we therefore predicted a similar l-dopa–mediated attenuation of fear and concomitant modulation of the extinction circuitry as in the mouse experiments. We focused on fear renewal as the most stringent test of the context-dependency of extinction (2), choosing to modify an earlier extinction expression paradigm (31) to make participants learn, on day 1, that one cue (CS+) predicted the UCS (electrotactile pain) in one context (conditioning context, A) but not in a different context in which no UCS was given (extinction context, B). A control cue (CS−) never predicted the UCS in either context. Learning was followed by administration of either 150 mg of l-dopa or placebo. On day 2, subjects were repeatedly shown the CS+ and the CS− in both contexts, presented in alternating order, in the absence of the UCS (Fig. 4A). On the basis of our prior data (31), we expected that the conditioning context A would promote renewal of fear to CS+ cues (Fig. 4A, test 2), whereas the extinction context B would promote expression of the extinction memory that is likewise associated with the CS+, observable as relatively reduced CRs (Fig. 4A, test 1). We used skin conductance responses (SCRs) as our major outcome measure. SCRs reflect the phasic arousal associated with fear responses (33) and therefore assess fear indirectly but objectively. 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. Indeed, the placebo group showed significantly larger differential SCRs (CS+ > CS−) in context A (test 2) than in context B (test 1) on day 2 (cue by context interaction in placebo: F 1,16 = 6.65, P = 0.02) (Fig. 4B, open bars). This pronounced renewal effect was significantly attenuated in the l-dopa group (cue by context by group interaction: F 1,31 = 5.23, P = 0.029) (Fig. 4B, filled bars). Further inspection suggested that the interaction was mainly due to relatively decreased responding to the CS+ in context A (post hoc t test: t 1,31 = 1.81, P = 0.082; two-tailed; Fig. 4B and Fig. S4, test 2; Table S4). Like in the mouse studies, direct l-dopa effects on renewal testing itself can again be excluded because of the short half-life of l-dopa in humans, too (18). Stronger renewal in the placebo participants was accompanied by deactivation of the left vmPFC to CS+ in conditioning context A, an effect that was cancelled in the l-dopa participants (Fig. 4C). This finding is of particular interest because deactivation of extinction areas during return-of-fear situations has been observed before in both rodents and humans (30, 34), and reduction of this deactivation has been linked to improved extinction expression (35, 36). vmPFC responses to the CS+ in context A showed a negative correlation with corresponding responses in the left dorsal amygdala in the l-dopa group (Fig. 4D). The dorsal and medial locations of this effect are in line with the described anatomical position of the CeM in humans (37). A trend-like positive correlation between activity in the identified amygdala peak effect voxel and SCRs to the CS+ in context A fit its presumed role in CR generation [R = 0.48, P = 0.06; two-tailed; after exclusion of one outlier (more than 2 SD < mean): R = 0.59, P = 0.02] (Fig. 4E). Hence, within a model in which down-regulation of the amygdala results from enhanced vmPFC activity (see above), l-dopa–mediated generalization of extinction appears to involve generalization of vmPFC activity. In exploratory analyses, we also observed an effect similar to the vmPFC result in the anterior hippocampus (l-dopa > placebo; −30, −14, −22; Z = 3.19, P < 0.001; uncorrected), a region that we have previously implicated in extinction memory expression in a similar paradigm (31). Anterior hippocampus responses, however, did not correlate with amygdala responses, suggesting a less direct role in extinction expression for this area compared with the vmPFC. There was an inverse group difference (l-dopa < placebo) in the posterior hippocampus (36, −28, −14; Z = 3.28, P < 0.001; uncorrected), an area linked with fear memory expression (31), but not in any other region of the fear network (e.g., dorsal anterior cingulate cortex).

Potential Mechanism. In rodents, extinction training induces spontaneous neural activity in the vmPFC (IL) in the hours following extinction, which predicts successful extinction expression 24 h later (38). Extinction training also lastingly elevates dopamine levels in the vmPFC (39). In the vmPFC, dopamine receptor expression is high and mainly confined to output layers (40), which are thought to convey fear inhibition after extinction (22, 23). Finally, responsiveness of vmPFC neurons to extinguished CSs is lastingly reduced in animals that have received a dopamine antagonist after extinction (16). Together, these findings lead to the hypothesis that dopamine-dependent spontaneous consolidation processes in the vmPFC determine later extinction expression by shaping vmPFC responding to CSs. Dopamine in the vmPFC probably derives from neurons originating in the ventral tegmental area (VTA) (41), and l-dopa enhances dopamine, but not noradrenaline, release in the frontal cortex (42). Like in the dopamine-dependent formation of long-term fear (13) and other memories (12), the dopaminergic midbrain is thus a likely candidate for participating in the boosting of extinction memory consolidation by l-dopa. To gain insight into these underlying mechanisms, we measured participants’ resting-state fMRI activity following extinction training on day 1, asking whether spontaneous activity in a dopaminergic-midbrain seed region (43) would correlate with spontaneous activity in the vmPFC. The 10-min scan was placed 45 min after drug administration when l-dopa should reach its maximum concentration in plasma and already well elevated levels in the brain (18, 44). l-dopa participants showed a significantly higher midbrain–vmPFC coupling than placebo participants (Fig. 5A). The amount of coupling predicted vmPFC responses to CS+ in context A 1 d later during the renewal test (test 2) in the l-dopa participants (R = 0.51, P = 0.027; two-tailed; Fig. 5B). There was no such relationship between the dopaminergic midbrain and the anterior hippocampus, suggesting that the vmPFC is the key area for l-dopa–mediated boosting of extinction consolidation. 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. On this basis, we suggest that the improved dopamine availability to midbrain dopamine neurons during consolidation in the presence of l-dopa translates into higher spontaneous dopamine transmission and concomitant spontaneous neural activity in the vmPFC, which in turn improves extinction memory expression in that area at later time points. The mechanism might involve dopamine-mediated enhancement of the local activity-dependent release or expression of proteins such as brain-derived neurotrophic factor (BDNF) (45), known to be critical for long-term memory storage generally (46) and for vmPFC-dependent extinction mechanisms in particular (47, 48). A potential source of BDNF in the vmPFC is the hippocampus (47), where long-term memory-promoting dopamine–BDNF interactions have been demonstrated (45, 46). In any case, our human data further support the conclusion from our rodent experiments that l-dopa administration directly after extinction makes extinction memories context-independent and protects from return of fear when a CS is encountered in a context that differs from the extinction context. Context-independency is not produced by, or has not been investigated in, other drugs tested in clinical studies for their ability to boost extinction-based therapy (49⇓–51).