ИСТИНА

Oxytocinergic system is a promising target for neuropsychological disorders as autism spectrum disorders, associated with disrupted socialization and “social anxiety”, decreased empathy manifestations and inadequate social reactions (detachment, aggressiveness etc.). We used a model of mild neurodevelopment disorder in rats, based on early postnatal expose of sodium valproate (VPA, 150 mg/kg, ip, on 6-12 PND), also known as a model of autism spectrum disorder [1], to assess effects of chronic intranasal oxytocin (OT) administration (10 µg/kg, 1-14 PND). After birth pups were divided into four groups: control, VPA, control-OT, and VPA-OT. We tested early development on 1-20 PND and exploratory and locomotor behavior in open field on PND 21.Then we performed tests to observe play behavior (29th PND) and social preference between sibling and unfamiliar animal (36th PND). Pups chronically exposed to VPA had decreased body weight and tail length, delayed reflexes of negative geotaxis and gait reflex compared to control group; oxytocin administration normalized gait reflex in group VPA-OT. Nevertheless, OT did not have effects on body measures of VPA pups. Control animals administrated with OT had negligible but significant impairment of negative geotaxis reflex. In open field animals from VPA group showed decreased locomotion combined with reduced exploratory behavior in comparison with control group, while animals administered OT (both control and VPA) did not exhibit significant behavioral changes relative to control group. In social preference test animals exposed to VPA demonstrated a reduction in social interactions: they showed decreased frequency of visiting section with a sibling and unfamiliar animal, and in play behavior, they acted more aggressively than control animals. Animals from VPA-OT spent less time interacting with another animal, and, similarly to VPA group, demonstrated more aggressive way of playing with less mutual grooming and tactile activity. Moreover, control-OT animals had a slight reduction of play behavior. Rats exposed to VPA had significantly expressed retardation in physical development, locomotor and exploratory activity, elevated anxiety and reduced social and play behavior. Oxytocin diminished anxiety of animals exposed to VPA, and partially enhanced maturing of motor reflexes; however, oxytocin increased the reduction of social behavior observed in VPA animals. Oxytocin did not have an influence on locomotion and exploration of control animals but reduced social interaction of control rats. VPA produce hyperexitatory effects in the brain and enhanced sensory gating, which can provide an explanation for increased anxiety and delayed social interaction [1]. Divergent social effects of chronic intranasal oxytocin administration already were described in mice. It can be explained by a reduction of OT receptors throughout the brain, induced by chronic administration of the peptide [2]. Therefore, animals exposed to VPA already had a deficiency of social interaction, consequently, OT administration aggravates this condition. Anxiolytic activity of OT provides by inhibition of amygdala activity [3] and reduction of stress-hormones release [4]. This study leads to the conclusion that postnatal VPA model provides opportunities to assess autistic-like features as anxiety and social interaction impairment and to challenge oxytocin usage in the treatment of autism spectrum disorders.