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In this study, we aim to explore the effects of two dopamine agonists (levodopa and bromocriptine) and two dopamine antagonists (tiapride and haloperidol) on fear extinction learning. To do so, young and healthy participants (18 to 35 years old) will undergo a three-day fear conditioning paradigm. Fear conditioning is an associative learning paradigm in which an originally neutral stimulus (conditioned stimulus (CS)) elicits fearful responses after being paired with an aversive stimulus (unconditioned stimulus (US)). Once the CS/US association is learned during fear acquisition training, repeated omission of the expected aversive US following CS presentations leads to a progressive decrease of conditioned fear responses (CR), that is extinction learning. In the recent literature, the dopaminergic system is thought to play an important function in mediating fear extinction due to its critical role in reward learning. A fundamental previous discovery was that the reward prediction error driving appetitive learning is signaled by a phasic dopamine increase originating in neurons of the ventral tegmental area (VTA; Schultz, 2016, for review). Because the unexpected omission of the US is rewarding (outcome better than expected), it has been proposed that the reward prediction error driving fear extinction learning is also mediated by dopamine release in the VTA (Kalisch et al., 2019). In humans, the application of levodopa immediately after extinction training augmented consolidation of the extinction memory trace (Gerlicher et al., 2018). Our goal is to assess the effects of dopaminergic and antidopaminergic drugs in extinction learning and recall. The drug will be administered prior to extinction training. Primary physiological outcome measures are changes in pupil size and skin conductance responses.

We hypothesize that the cerebellum is involved in the processing of reward prediction errors in cooperation with the ventral tegmental area (VTA), and that these reward prediction errors drive fear extinction learning. To study this proposed interaction, we use a 3-day fear conditioning paradigm in young and healthy controls in a 7T MRI scanner. Fear extinction is studied through Pavlovian fear conditioning paradigms, in which the presentation of a neutral conditioned stimulus (CS) is paired to an aversive unconditioned stimulus (US), so that a fear association is learned between the CS and the US. As a result, the CS is no longer neutral and generates a conditioned fear response (e.g. increased sweating and enlarged pupil size). When the CS is subsequently no longer paired with the US, fear extinction learning occurs, which inhibits the fear association and dampens the conditioned fear response. An important event for fear extinction learning is the unexpected omission of the US, which is a better than expected outcome, resulting in reward prediction errors (Kalisch et al., 2019). Research on rodents has shown that the VTA encodes these reward prediction errors during fear extinction (Salinas-Hernández et al., 2018). On the other hand, the cerebellum is known to process prediction errors in the motor domain, and this is increasingly thought to be true for cognitive and emotional domains as well (Popa and Ebner, 2019). In accordance with this, Ernst and colleagues found that the human cerebellum has prediction error related activity during the unexpected omission of the US (Ernst et al., 2019). In addition, the cerebellum and the VTA are connected bidirectionally (Ikai et al., 1992; Carta et al., 2019). Taken together, an interaction between the cerebellum and VTA might be important to process reward prediction errors which could drive fear extinction.

[This corrects the article DOI: 10.3389/fnsys.2023.1166166.]., (Copyright © 2024 Doubliez, Nio, Senovilla-Sanz, Spatharioti, Apps, Timmann and Lawrenson.)