Long-term exposure to intranasal oxytocin in a mouse autism model.
Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.
1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.
K L
KL
Bales
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
M
M
Solomon
Department of Psychiatry and Pediatrics, University of Minnesota, Minneapolis, MN, USA.
S
S
Jacob
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
J N
JN
Crawley
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
J L
JL
Silverman
1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.
R H
RH
Larke
1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.
E
E
Sahagun
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
K R
KR
Puhger
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
M C
MC
Pride
1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.
S P
SP
Mendoza
D000281:Administration, Intranasal; D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010121:Oxytocin / Q000008:administration & dosage / Q000494:pharmacology*; D012737:Sex Factors; D012919:Social Behavior
D010121:Oxytocin