Acute, chronic and conditioned effects of intranasal oxytocin in the mu
opioid receptor knockout mouse model of autism: social context matters
Abstract
Background and Purpose Autism Spectrum Disorders (ASD) are
neurodevelopmental disorders whose diagnosis relies on deficient social
interaction and communication together with repetitive behaviours.
Multiple studies have highlighted the potential of oxytocin (OT) to
ameliorate behavioural abnormalities in animal models and subjects with
ASD. Clinical trials, however, yielded disappointing results. Our study
aimed at challenging hypotheses accounting for such negative results by
assessing the behavioural effects of different regimens of OT
administration in the Oprm1 null mouse model of ASD. Experimental
Approach We assessed the effects of intranasal OT injected once at
different doses and time points following administration, or
chronically, on ASD-related behaviours in Oprm1+/+ and Oprm1-/- mice. We
then tested whether pairing intranasal OT injection with social
experience would influence its outcome on ASD-like core symptoms, and
measured gene expression in several regions of the reward/social
circuit. Key Results Acute intranasal OT improved social behaviour in
Oprm1-/- mice at a moderate dose (0.3 IU) shortly after administration
(5 min). Effects on non-social behaviours were limited. Chronic OT at
this dose maintained beneficial effects in Oprm1 null mice but was
deleterious in wild-type mice. Finally, improvements in the social
behaviour of Oprm1-/- mice were greater and longer lasting when OT was
administered in a social context, while the expression of OT and
vasopressin receptor genes, as well as marker genes of striatal
projection neurons, was suppressed. Conclusions and implications Our
results highlight the importance of considering dosage and social
context when evaluating the effects of OT treatment in ASD.