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Long-term exposure to intranasal oxytocin in a mouse autism model.

Bales KL, Solomon M, Jacob S, Crawley JN, Silverman JL, Larke RH, Sahagun E, Puhger KR, Pride MC, Mendoza SP - Transl Psychiatry (2014)

Bottom Line: Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.

ABSTRACT
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.

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Three-chambered social interaction. (a) Male B6 mice treated with either saline (n=11) or OT (n=8) spent more time in the chamber with the novel mouse than in the chamber with the novel object (saline: P<0.001, OT: P=0.017), as did saline-treated male BTBR mice (n=12, P=0.008). OT-treated BTBR males (n=10) did not differ between the novel mouse over the novel object. (b) Female B6 mice treated with either saline (n=12) or OT (n=10) spent more time in the chamber with the novel mouse over the novel object (saline: P<0.0001; OT: P<0.001), whereas female BTBR mice which received either treatment (n=12 for saline and n=10 for OT) did not. (c) Male mice of both strains and all treatments spent significantly more time sniffing a novel mouse than a novel object (all P<0.05). (d) Both OT- and saline-treated B6 females spent more time sniffing a novel mouse than a novel object (P<0.01). However, OT-treated BTBR females spent significantly more time sniffing the novel mouse than the novel object (P=0.004), whereas saline-treated BTBR females did not. OT, oxytocin.
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fig4: Three-chambered social interaction. (a) Male B6 mice treated with either saline (n=11) or OT (n=8) spent more time in the chamber with the novel mouse than in the chamber with the novel object (saline: P<0.001, OT: P=0.017), as did saline-treated male BTBR mice (n=12, P=0.008). OT-treated BTBR males (n=10) did not differ between the novel mouse over the novel object. (b) Female B6 mice treated with either saline (n=12) or OT (n=10) spent more time in the chamber with the novel mouse over the novel object (saline: P<0.0001; OT: P<0.001), whereas female BTBR mice which received either treatment (n=12 for saline and n=10 for OT) did not. (c) Male mice of both strains and all treatments spent significantly more time sniffing a novel mouse than a novel object (all P<0.05). (d) Both OT- and saline-treated B6 females spent more time sniffing a novel mouse than a novel object (P<0.01). However, OT-treated BTBR females spent significantly more time sniffing the novel mouse than the novel object (P=0.004), whereas saline-treated BTBR females did not. OT, oxytocin.

Mentions: During the social approach phase, male B6 spent significantly more time in the chamber with the novel mouse as compared with time spent in the chamber with the novel object, in both the saline-treated group (t10=−5.118, P<0.001) and the OT-treated group (t7=−3.111, P=0.0171; Figure 4a), as expected from many previous publications. Unexpectedly, male BTBR treated with saline spent more time in the chamber with the novel mouse than in the chamber with the novel object (t11=−3.188, P=0.008). Male BTBR treated with OT spent approximately equal time in the two side chambers (t10=−1.414, P=0.188), although a trend appears for more time in the novel mouse chamber. It is possible that this unusual sociability in male BTBR mice dosed for 30 days with intranasal saline was because of the stress of repeated handling and treatments (see discussion).


Long-term exposure to intranasal oxytocin in a mouse autism model.

Bales KL, Solomon M, Jacob S, Crawley JN, Silverman JL, Larke RH, Sahagun E, Puhger KR, Pride MC, Mendoza SP - Transl Psychiatry (2014)

Three-chambered social interaction. (a) Male B6 mice treated with either saline (n=11) or OT (n=8) spent more time in the chamber with the novel mouse than in the chamber with the novel object (saline: P<0.001, OT: P=0.017), as did saline-treated male BTBR mice (n=12, P=0.008). OT-treated BTBR males (n=10) did not differ between the novel mouse over the novel object. (b) Female B6 mice treated with either saline (n=12) or OT (n=10) spent more time in the chamber with the novel mouse over the novel object (saline: P<0.0001; OT: P<0.001), whereas female BTBR mice which received either treatment (n=12 for saline and n=10 for OT) did not. (c) Male mice of both strains and all treatments spent significantly more time sniffing a novel mouse than a novel object (all P<0.05). (d) Both OT- and saline-treated B6 females spent more time sniffing a novel mouse than a novel object (P<0.01). However, OT-treated BTBR females spent significantly more time sniffing the novel mouse than the novel object (P=0.004), whereas saline-treated BTBR females did not. OT, oxytocin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4259989&req=5

fig4: Three-chambered social interaction. (a) Male B6 mice treated with either saline (n=11) or OT (n=8) spent more time in the chamber with the novel mouse than in the chamber with the novel object (saline: P<0.001, OT: P=0.017), as did saline-treated male BTBR mice (n=12, P=0.008). OT-treated BTBR males (n=10) did not differ between the novel mouse over the novel object. (b) Female B6 mice treated with either saline (n=12) or OT (n=10) spent more time in the chamber with the novel mouse over the novel object (saline: P<0.0001; OT: P<0.001), whereas female BTBR mice which received either treatment (n=12 for saline and n=10 for OT) did not. (c) Male mice of both strains and all treatments spent significantly more time sniffing a novel mouse than a novel object (all P<0.05). (d) Both OT- and saline-treated B6 females spent more time sniffing a novel mouse than a novel object (P<0.01). However, OT-treated BTBR females spent significantly more time sniffing the novel mouse than the novel object (P=0.004), whereas saline-treated BTBR females did not. OT, oxytocin.
Mentions: During the social approach phase, male B6 spent significantly more time in the chamber with the novel mouse as compared with time spent in the chamber with the novel object, in both the saline-treated group (t10=−5.118, P<0.001) and the OT-treated group (t7=−3.111, P=0.0171; Figure 4a), as expected from many previous publications. Unexpectedly, male BTBR treated with saline spent more time in the chamber with the novel mouse than in the chamber with the novel object (t11=−3.188, P=0.008). Male BTBR treated with OT spent approximately equal time in the two side chambers (t10=−1.414, P=0.188), although a trend appears for more time in the novel mouse chamber. It is possible that this unusual sociability in male BTBR mice dosed for 30 days with intranasal saline was because of the stress of repeated handling and treatments (see discussion).

Bottom Line: Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychology, University of California, Davis, Davis, CA, USA [2] California National Primate Research Center, University of California, Davis, Davis, CA, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus