Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner

Rationale

Oxytocin (OXT) has been proposed as a potential therapeutic agent for post-traumatic stress disorder (PTSD).

Objectives

We aimed to verify whether pharmacological manipulation of the brain OXT system affects cued fear conditioning and fear extinction.

Methods

Male rats and mice were intracerebroventricularly administered synthetic OXT (rats, 0.1 or 1.0 μg/5 μl; mice, 0.1 or 0.5 μg/2 μl) and/or an OXT receptor antagonist (OXTR-A; rats, 0.75 μg/5 μl) either prior to fear conditioning or extinction training.

Results

Preconditioning administration of OXT did not affect fear conditioning in rats, but decreased fear expression and facilitated fear extinction. In contrast, preconditioning blockade of OXT neurotransmission by OXTR-A did not affect fear conditioning or fear expression, but impaired fear extinction. When administered before extinction training, OXT impaired fear extinction in both rats and mice, indicating that the effects of OXT on fear extinction are conserved across species. This impairment was OXTR-mediated, as the inhibitory effect of OXT on fear extinction was abolished by prior treatment with OXTR-A. The impaired fear extinction was not a result of reduced locomotion in rats, whereas an apparent decrease in fear expression and facilitation of fear extinction with the higher OXT dose in mice was the result of behavioral hyperactivity.

Conclusions

These results suggest that increasing OXT neurotransmission during traumatic events is likely to prevent the formation of aversive memories. In contrast, OXT treatment before fear extinction training, which would be the comparable timepoint for psychotherapy in PTSD patients, rather delays fear extinction and, therefore, caution is needed before recommending OXT for the treatment of PTSD.