Oxytocin enhancement of fear extinction: a new target for facilitating exposure-based treatments?

It has been more than a decade since Ressler et al. published the first demonstration of facilitation of exposure-based therapy with the N-methyl-D-aspartate co-agonist D-cycloserine (1). Since that pivotal study, there has been a surge of research to identify additional targets that enhance fear extinction for adjunctive treatment strategies. Potential pathways include catecholamines, endocannabinoids, and various neuropeptide systems and epigenetic pathways (1). Among the neuropeptide candidates, oxytocin (OT) has gained attention as a modulator of conditioned fear processes including fear extinction. OT receptors are located on neural circuits mediating fear learning and extinction, and there is substantial preclinical literature supporting modulatory effects of OT receptor signaling on conditioned fear learning, recall, and extinction (2). Furthermore, the putative prosocial effects of OT make it attractive as an adjunctive treatment for behavioral therapies, as it may facilitate patient-therapist alliance and acceptability of treatment. Initial support for the hypothesis that OT may enhance fear extinction in humans came from a study from our laboratory, which found that OT administration before extinction training significantly increased 24-hour extinction recall. However, the mechanism by which OT affects extinction in humans is unknown. In this issue of Biological Psychiatry, Eckstein et al. (3) address the question of neural mechanisms of OT effects on extinction in important ways. They studied 62 healthy men who were randomly assigned to receive either intranasal OT or placebo spray after a fear conditioning procedure. Participants then received fear extinction training 30 min after OT treatment. Compared with men given placebo, participants given OT exhibited increased conditioned fear responses in the early phase of extinction, but by the last training phase they showed significantly lower conditioned fear responses than the placebo group. Despite initial increases in fear responding, the OT-treated group had significantly enhanced extinction learning by the end of training. The authors showed that OT affected activity in neural circuits associated with fear processing, including the prefrontal cortex (PFC) and the amygdala. The findings of Eckstein et al. are intriguing in that they did not implicate OT engagement of the well-known PFC region implicated in extinction, the ventromedial PFC, but instead a dorsal region of the mid-medial PFC. The mid-medial PFC was activated only during initial fear extinction training, when fear responding was significantly higher than in the placebo group, but not during the second phase corresponding to lower fear responses. The dorsolateral PFC is associated with deliberate regulation of responses to conditioned cues, whereas the dorsomedial PFC is more commonly associated with fear