The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample

Abstract

Rationale: To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans.

Objectives: The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction.

Methods: A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall.

Results: Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo.

Conclusions: The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

Figure 1

(A) Schematic of the fear potentiated startle procedure listing all three conditioning and extinction phases and illustrating a prototypical trial block and trial. (B) Timeline of all experimental assessments.

Figure 2

(A) Potentiated startle magnitudes for the Acquisition Phase before treatment. *p < .05 vs. CS−. (B) Potentiated startle magnitude to the CS+ during Late Acquisition and Early, Mid and Late Extinction phase by Treatment Group. *p < .05 vs. placebo. # p < .05 vs. Early Extinction phase responding within group. (C) Potentiated startle magnitudes to the CS+ during Early extinction depicted in two-trial blocks. *p<0.05, main effect of oxytocin. Data are depicted as mean±SEM difference scores in peak startle magnitude during CS+ or CS− trials compared to noise alone trials.

Figure 2

(A) Potentiated startle magnitudes for the Acquisition Phase before treatment. *p < .05 vs. CS−. (B) Potentiated startle magnitude to the CS+ during Late Acquisition and Early, Mid and Late Extinction phase by Treatment Group. *p < .05 vs. placebo. # p < .05 vs. Early Extinction phase responding within group. (C) Potentiated startle magnitudes to the CS+ during Early extinction depicted in two-trial blocks. *p<0.05, main effect of oxytocin. Data are depicted as mean±SEM difference scores in peak startle magnitude during CS+ or CS− trials compared to noise alone trials.

Figure 3

Expectancy ratings across the last half of the acquisition phase (Late Acq) and the entire extinction phase (Early, Mid, and Late Ext). 1 = expect the US, 0 = uncertain, −1 = do not expect the US. Data are depicted as mean±SEM ratings by trial.

Figure 4

Extinction recall index during the Recall phase by Treatment Group (see text for equation). *p < .05. Data are depicted as mean index scores±SEM. Inset: Maximum potentiated startle magnitudes during the Acquisition Phase by Treatment Group and potentiated startle magnitudes for the Recall Phase by Treatment Group. Data are depicted as mean±SEM difference scores in peak startle magnitude during CS+ trials compared to noise alone trials