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

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.

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

“…Caution should be exercised before administering to children and young adults as one study suggested that behavioral impairments occur following chronic intranasal treatment in developing prairie voles [240]. While no major deleterious effects on social behavior were reported following chronic intranasal administration of OT (at doses being used in clinical trials) in wild-type mice and a mouse model of autism spectrum disorder [241], additional studies should address the long-term neuroendocrine and behavioral effects following multiple doses of OT in developing animals and nonhuman primates [24,240].…”

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Similarly, chronic intranasal OT treatment resulted in a reduction of social behaviors and concurrent reductions of OTR binding in the nAcc, amygdala, and anterior olfactory nucleus amongst other brain regions (Huang et al, 2014). Moreover, in a mouse model of ASD, chronic intranasal OT administration did not lead to improvements in social behaviors (Bales et al, 2014). Lastly, exposure to ELS seems to alleviate or even reverse the presumed beneficial effects of intranasal OT treatment in humans (Bakermans-Kranenburg and Van Ijzendoorn, 2013; Grimm et al, 2014).…”

Oxytocin in General Anxiety and Social Fear: A Translational Approach

“…However, relevant basic studies are rare, and those performed reveal that chronic OXT effects strongly depend on the dose and duration of application, are likely to vary between male and female subjects (65)(66)(67)(68)(69)(70)(71)(72), and are dependent upon the innate level of anxiety (65). For example, in male mice, chronic icv infusion of OXT (10 ng/hour) over 2 weeks induced a robust increase in anxiety-related behavior in two independent behavioral tests, whereas a tenfold lower dose did not alter anxiety (67).…”