Dopamine D2/3 receptors and functional connectivity during fear extinction: A PET-fMRI study

The ability to learn what is dangerous in the environment and what no longer exerts a threat is essential for survival. The latter process is studied using Pavlovian fear extinction, the repeated presentation of a feared stimulus that gradually attenuates the fear response. Dysregulation of the extinction process is implicated in a range of anxiety disorders, yet the neurobiological mechanisms supporting extinction learning in humans remain incompletely mapped, particularly with respect to the modulating role of dopamine.

To examine the role of baseline dopamine D2/3 receptors in fear extinction and responses to unconditioned stimulus (US) omission.

Fifteen healthy adults completed a differential cued Pavlovian conditioning paradigm, including one conditioned stimulus (CS+) paired with an aversive electric shock US and one never paired (CS-). Participants underwent [¹¹C]raclopride positron emission tomography (PET) of baseline dopamine D2/3 receptor availability prior to fear acquisition, and subsequent fear extinction with skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) continuously recorded.

SCR and neural activations indicated remaining conditioned responding during extinction, with greater responses to CS+ than to CS- in the insula and frontoparietal regions. Higher baseline dopamine D2/3 receptor availability in the amygdala was associated with lower fear-related (CS+> CS-) connectivity between the right amygdala and the right anterior insula. Higher differential SCR (CS+> CS-) was associated with reduced functional connectivity between the right amygdala and left anterior insula. Lower baseline dorsal striatal D2/3 receptor availability was associated with greater mean SCRs to US omission. No associations were detected between baseline D2/3 receptor availability and extinction-related reductions of conditioned SCR or neural responses across trials.

These findings suggest that individual differences in dopamine D2/3 receptor availability are related to threat processing and responses to US omission, but may be less strongly associated with extinction learning itself.