Intranasal Oxytocin Reduces Anxiety in Male Autism Model Rats But Worsens Social Behavior | Research

The takeaway

Intranasal oxytocin reduced anxiety in male rats from a prenatal valproic acid autism model but increased anxiety in females and surprisingly impaired social interactions in both sexes — highlighting sex-dependent and potentially counterproductive effects.

Social behavior worsened
Oxytocin — proposed as a "social hormone" treatment for autism — paradoxically impaired social interactions in both male and female rats in an autism model

What the researchers found

Intranasal oxytocin was anxiolytic for VPA males but anxiogenic for VPA females. In both sexes, oxytocin impaired social interactions in the sociability test and failed to improve sociosexual deficits. Prenatal VPA produced sex-specific behavioral deficits.

Why it matters

Oxytocin is being given to autistic children off-label. This study raises important safety concerns: oxytocin may help anxiety but could paradoxically worsen social behavior, and effects differ dramatically between sexes.

The numbers in context

500 mg/kg VPA GD12; 0.8 IU/kg oxytocin intranasal; anxiolytic in males; anxiogenic in females; impaired sociability both sexes

How the study worked

Animal study. Prenatal valproic acid (500 mg/kg, gestational day 12) in Long Evans rats. Intranasal oxytocin (0.8 IU/kg) or saline 30-60 min before testing. Elevated plus maze (anxiety), sociability, partner preference, ultrasonic vocalizations, and scent marking assessed.

Who was studied

Long Evans rat pups prenatally exposed to valproic acid (autism model)

What this study cannot tell us

VPA rat model may not fully replicate human ASD. Single oxytocin dose and timing. Acute administration — chronic effects may differ. Intranasal delivery in rats is imprecise compared to human nasal sprays.

How to read the evidence

Moderate evidence: well-designed animal study with multiple behavioral measures and both sexes, but VPA model has limitations and results are from acute dosing.

When this study was published

Published 2021. Oxytocin for ASD continues to show mixed results in human trials, consistent with these animal findings.

The bigger picture

These mixed and sex-dependent results mirror the inconsistency of human oxytocin trials in ASD. They suggest oxytocin is not a simple "social hormone" fix for autism and that its effects on anxiety versus social behavior may be dissociable or even opposing.

Questions still open

Does chronic rather than acute oxytocin administration produce different social behavior outcomes?
Should oxytocin clinical trials in ASD stratify by sex given these dramatic sex differences?
Could oxytocin be useful specifically for ASD-associated anxiety while other approaches address social deficits?

Common questions

Should I give my autistic child oxytocin nasal spray?

This study and others suggest caution. While oxytocin may help with anxiety in some individuals (particularly males), it paradoxically worsened social interactions in this animal model. Effects also differed dramatically between sexes. Discuss with a specialist before trying oxytocin for ASD.

Why would oxytocin worsen social behavior?

Oxytocin's effects are more complex than "boosting sociability." It increases sensitivity to social cues, which in some contexts or individuals may cause social withdrawal or anxiety. The optimal dose, timing, and patient characteristics for beneficial effects are still being determined.

Read the original research

Prenatal exposure to valproic acid and treatment with intranasal oxytocin have sex-specific effects on behavior in Long Evans rats.

Behavioural pharmacology, 32(7), 561-570

View on PubMed ↗Publisher’s paper ↗

Citation

Harding, Shannon M; Masters, Ellen C; D'Agata, Christina M; Agudelo Rivera, Aura C; Smith, Emma C. (2021). Prenatal exposure to valproic acid and treatment with intranasal oxytocin have sex-specific effects on behavior in Long Evans rats.. Behavioural pharmacology, 32(7), 561-570. https://doi.org/10.1097/FBP.0000000000000650