Autistic-like behaviors are attenuated by agmatine consumption during pregnancy: Assessment of oxidative stress profile and histopathological changes in the prefrontal cortex and CA1 region of the hippocampus.

Objectives: Due to the crucial role of polyamines during fetal growth and development, we aimed to determine the effect of prenatal administration of agmatine, an endogenous active metabolite of arginine, and a nutritional supplement, on autistic-like behaviors, oxidative-anti-oxidative profile, and histopathological changes of the prefrontal cortex (PFC) and CA1 area of the hippocampus in valproic acid (VPA) model of autism in male rats. Materials and Methods: VPA was injected intraperitoneally on embryonic days (ED) 12.5, and the pregnant rats were gavaged with agmatine between E6.5 to E18.5 (13 days), at doses of 0.001, 0.01, and 0.1 mg/kg. The autism-like behaviors and memory of male pups were analyzed via open-field, three-chamber, and novel object recognition tests. Serum oxidative stress and the histological changes in the PFC and CA1 were assessed at the end of the study. Results: The results suggest that prenatal agmatine reduced autistic-like behaviors by decreasing cell loss in CA1 and PFC. We observed no alterations in superoxide dismutase (SOD) level and total anti-oxidant capacity (TAC) between groups. VPA decreased catalase (CAT) activities, while agmatine decreased malondialdehyde (MDA) activity. Conclusion: Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

Effects of Nicotine Administration in an Enriched Environment on the Behavior of Male MK-801-Exposed Rats.

Background: Smoking is more common in patients with schizophrenia than in healthy populations. Some controversial hypotheses connect the disease with the high prevalence of smoking. Moreover, environmental factors affect the severity of the positive and negative symptoms of schizophrenia. The current study aimed to assess the effect of enriched environment (EE) and nicotine on the MK-801 animal model of schizophrenia. Methods: Male Wistar rat pups randomly received saline or MK-801 (dose:1 mg/kg) for five days from the sixth postnatal day (P) until the tenth. The pups were placed in EE or standard cages (SCs) after weaning (P21). Morris water maze (MWM) was used to assess spatial learning and memory. The rats received 0.6 mg/kg nicotine twice for three days at the end of the second month and were examined in an open-field box and three-chamber social interaction test. Findings: MK-801 rats' behaviors were the same as those of the saline rats when they were exposed to nicotine. No positive effects of EE were observed when the animals were exposed to nicotine. Conclusion: The results suggested that nicotine decreased schizophrenia-like symptoms and covered the positive effects of EE.

Nicotine-conditioned place preference, reversal learning and social interaction in MK-801-induced schizophrenia model: Effects of post-weaning enriched environment.

Based on the clinical observations of severe cognitive deficits in schizophrenia patients and the relationship between environmental parameters and the severity of schizophrenia symptoms, the present study investigated these parameters in an dizocilpine (MK-801)-induced schizophrenia model in rats. In addition to, it evaluated whether a post-weaning enriched environment (EE) would affect the nicotine-induced conditioned place preference (CPP) and the motor and cognitive deficits caused by MK-801 treatment. Male Wistar rat pups were injected peritoneally with MK-801 (1 mg/kg) on a daily basis between the 6th and the 10th postnatal days (P) and were exposed to either an enriched or a standard cage from P21 until the end of the experiments. The rats were evaluated in open-field and three-chamber social interaction tests. Moreover, spatial and reversal learning was assessed by the Morris water maze (MWM). The animals were conditioned with 0.6 mg/kg nicotine and tested for CPP. Increased self-grooming, exploratory behaviour, potentiated nicotine-CPP and decreased social behaviours, delayed spatial learning and memory and impaired reversal learning in the water maze were observed in the MK-801 treatment group. Housing in an EE improved cognitive and behavioural deficits associated with postnatal MK-801 treatment. The results suggested that neonatal N-methyl-d-aspartate (NMDA) receptor hypofunction may cause susceptibility to these behaviours and indicated the importance of environmental conditions in the development of schizophrenia and probably other neuropsychiatric disorders.

An overview of modeling and behavioral assessment of autism in the rodent.

Autism Spectrum Disorders (ASDs) are common neurodevelopmental disorders with a growing incidence that generally present in the first 3 years of life. Behavioral symptoms, including impaired social interaction and increased repetitive or stereotypic movements, are hallmark characteristics of autism. Animal models are research tools used to study the biology of the disease and to develop new therapeutic approaches. The complexity of the etiology of autism makes it challenging to develop a comprehensive animal model that accurately mimics different clinical aspects of autism. Here, we reviewed the literature on modeling and behavioral assessment of autism in the rodent, and focused on ASD behavioral phenotypes that can be modeled in rodents. These animal models can be effective in gaining a better understanding of the pathophysiology of the disease.

Improvement of autistic-like behaviors in adult rats prenatally exposed to valproic acid through early suppression of NMDA receptor function.

RATIONALE: Autism spectrum disorder (ASD), the fastest growing neurodevelopmental disorder, is characterized by social deficits, repetitive/stereotypic activity, and impaired verbal and nonverbal communication and is commonly diagnosed at early stages of life. Based on the excitatory-inhibitory imbalance theory of autism, some recent animal experiments have reported amelioration in autistic-like phenotypes in adult animals following acute treatment of NMDA antagonists. However, we suggested the neonatal period as a critical period for NMDA antagonist intervention. OBJECTIVES: This experiment was designed to determine the role of postnatal MK-801, an NMDA receptor blocker, in the prenatal valproic acid (VPA) rat model of ASD. METHODS: The model of autism was induced by subcutaneous administration of valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. The effects of MK-801 (0.03 mg/kg, from postnatal day 6-10) in correcting ASD-associated behaviors in male offspring were assessed by open-field, three-chambered social interaction tests. Moreover, the nociceptive threshold was measured by tail flick and hot plate. Behavioral tests were performed on PND 55-60. Nissl staining was performed to confirm the safety of 0.03 mg/kg MK-801 for the brain. RESULTS: We reported that MK-801 rescued social deficits, repetitive behaviors (self-grooming), anxiety-related behavior, and the low nociceptive threshold in the VPA-treated rats. Further, histological examination showed that there were no significant differences among all the groups in terms of the neuronal survival rate. CONCLUSIONS: Our results showed that postnatal low-dose MK-801 improved ASD-associated behaviors in the VPA-treated rats and that early exposure to NMDA antagonist resulted in permanent changes in adult behavior.