Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism

Abstract

Background and objectives: The hormone oxytocin (OXT) has already been reported in both human and animal studies for its promising therapeutic potential in autism spectrum disorder (ASD), but the comparative effectiveness of various administration routes, whether central or peripheral has been insufficiently studied. In the present study, we examined the effects of intranasal (IN) vs. intraperitoneal (IP) oxytocin in a valproic-acid (VPA) autistic rat model, focusing on cognitive and mood behavioral disturbances, gastrointestinal transit and central oxidative stress status. Materials and Methods: VPA prenatally-exposed rats (500 mg/kg; age 90 days) in small groups of 5 (n = 20 total) were given OXT by IP injection (10 mg/kg) for 8 days consecutively or by an adapted IN pipetting protocol (12 IU/kg, 20 μL/day) for 4 consecutive days. Behavioral tests were performed during the last three days of OXT treatment, and OXT was administrated 20 minutes before each behavioral testing for each rat. Biochemical determination of oxidative stress markers in the temporal area included superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). A brief quantitative assessment of fecal discharge over a period of 24 hours was performed at the end of the OXT treatment to determine differences in intestinal transit. Results: OXT improved behavioral and oxidative stress status in both routes of administration, but IN treatment had significantly better outcome in improving short-term memory, alleviating depressive manifestations and mitigating lipid peroxidation in the temporal lobes. Significant correlations were also found between behavioral parameters and oxidative stress status in rats after OXT administration. The quantitative evaluation of the gastrointestinal (GI) transit indicated lower fecal pellet counts in the VPA group and homogenous average values for the control and both OXT treated groups. Conclusions: The data from the present study suggest OXT IN administration to be more efficient than IP injections in alleviating autistic cognitive and mood dysfunctions in a VPA-induced rat model. OXT effects on the cognitive and mood behavior of autistic rats may be associated with its effects on oxidative stress. Additionally, present results provide preliminary evidence that OXT may have a balancing effect on gastrointestinal motility.

Transcriptome Analysis in Hippocampus of Rats Prenatally Exposed to Valproic Acid and Effects of Intranasal Treatment of Oxytocin

“…In our previous studies, we had reported that prenatal VPA exposure impairs learning and long-term potentiation (LTP) in the hippocampus of rats and that chronic administration of intranasal OXT ameliorates learning disabilities ( 26 , 27 ). In line with our observations, intranasal administration of OXT blocked the learning disability in prenatally VPA-exposed or restraint stress-exposed animal models ( 28 – 30 ). In contrast, Hara et al demonstrated that a single dose of OXT was effective for social impairment only for a short period and not for memory impairment ( 31 ).…”

Intraamygdaloid Oxytocin Reduces Anxiety in the Valproate-Induced Autism Rat Model

“…Moreover, an intranasal OT treatment was shown to improve the autistic-like behavior in mice in the open field test, the marble burying test, the tail suspension test, and the three-chamber social interaction test [ 34 ]. Intranasal OT treatment has been reported to alleviate autistic cognitive and mood dysfunctions in the VPA-induced rodent model of autism [ 35 ]. The aforementioned study found that OT improved the oxidative status and ameliorated short-term memory and depressive manifestations [ 35 ].…”

“…Intranasal OT treatment has been reported to alleviate autistic cognitive and mood dysfunctions in the VPA-induced rodent model of autism [ 35 ]. The aforementioned study found that OT improved the oxidative status and ameliorated short-term memory and depressive manifestations [ 35 ]. Evidence was found that central administration of OT was more effective than peripheral administration [ 35 ].…”

“…The aforementioned study found that OT improved the oxidative status and ameliorated short-term memory and depressive manifestations [ 35 ]. Evidence was found that central administration of OT was more effective than peripheral administration [ 35 ]. In humans, OT has been also demonstrated to promote social behavior in high-functioning ASD patients [ 36 ].…”

The Role of Intraamygdaloid Oxytocin and D2 Dopamine Receptors in Reinforcement in the Valproate-Induced Autism Rat Model

“…There is currently no cure for autism, but in some respects, behavioral therapies based on reward-based reinforcement learning seem effective [ 65 ]. Studies also indicate the potential role of OT in ameliorating autistic symptoms and OT has been reported to play a role in social reward mechanisms [ 66 , 67 , 68 ]. Our present findings suggest that intraamygdaloid OT is involved in non-social positive reinforcing mechanisms under the VPA-induced autism rat model.…”