Agmatine ameliorates valproic acid-induced depletion of parvalbumin-positive neuron.

Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with unknown etiology. Dysfunction of several brain areas including the prefrontal cortex (PFC), hippocampus, and cerebellum is involved in cognitive and behavioral deficits associated with ASD. Several studies have reported a reduction in the number of parvalbumin-immunoreactive (PV+) neurons in brain areas of ASD patients and animal models such as a shank mutant mouse model and rodents receiving fetal valproic acid (VPA) administration. Developing therapeutic interventions that restore PV interneurons can be the future therapeutic approach to ASD. The present study examined the possible effect of agmatine (AG), an endogenous NMDA antagonist, on the number of PV+ neurons in a VPA animal model of autism. The therapeutic effects of AG in ameliorating ASD-like behaviors were previously reported in VPA rats. AG was gavaged at dosages of 0.001, 0.01, and 0.1 mg/kg from gestational day (GD) 6.5 to 18.5, and the number of PV interneurons was analyzed by immunohistochemistry in the 1-month-old rats. Prenatal VPA (GD 12.5) or AG led to a decrease of PV neurons in the PFC, Cornu ammonia (CA1), and molecular layers (MLs) of the cerebellum. However, exposure to AG restored the PV population induced by VPA. AG may modify underlying neuronal mechanisms resulting in the increased survival or restoration of the PV population.

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.

Comparable Efficacy of Repeated Transcranial Direct Current Stimulation, Cognitive Behavioral Therapy, and Their Combination in Improvement of Cold and Hot Cognitive Functions and Amelioration of Depressive Symptoms.

ABSTRACT: This study aimed to evaluate the effectiveness of repeated transcranial direct current stimulation (rtDCS), cognitive behavioral therapy (CBT), and their combination (rtDCS-CBT) in the treatment of cognitive dysfunction, social cognition, and depressive symptoms in women diagnosed with major depressive disorder (MDD). A total of 40 female participants with MDD were randomly assigned to one of four groups: rtDCS, CBT, rtDCS-CBT, and a control group. The participants' depressive symptoms, executive functions, and social cognition were assessed at baseline, preintervention, postintervention, and during a 1-month follow-up. The rtDCS group received 10 sessions of anodal dorsolateral and cathodal ventromedial prefrontal cortex (2 mA for 20 minutes). The CBT group received 10 sessions of traditional CBT, whereas the combined group received CBT after the tDCS sessions. The results of the analysis of variance indicated that all intervention groups demonstrated significant improvements in depressive symptoms, cognitive dysfunction, and social cognition compared with the control group (all p < 0.001). Furthermore, the rtDCS-CBT group exhibited significantly greater reductions in depressive symptoms when compared with each intervention alone (all p < 0.001). Notably, working memory improvements were observed only in the rtDCS group ( p < 0.001). In conclusion, this study suggests that both CBT and tDCS, either individually or in combination, have a positive therapeutic impact on enhancing executive functions, theory of mind, and depressive symptoms in women with MDD.

Hydroalcoholic extract of Passiflora incarnata improves the autistic-like behavior and neuronal damage in a valproic acid-induced rat model of autism.

Experimental autism in rodents can be caused by prenatal valproic acid (VPA) exposure. Some diseases, such as attention-deficit hyperactivity disorder (ADHD), insomnia, opiate withdrawal, and generalized anxiety disorder can be treated by consuming Passiflora incarnata, due to the possession of bioactive compounds like alkaloids, phenols, and flavonoids. The present study aims to investigate the role of the hydroalcoholic extract of Passiflora incarnata in behavioral and oxidative stress aberrations induced by VPA. On the gestational day (GD), 12.5, pregnant Wistar rats received VPA (600 mg/kg subcutaneously). Male pups were treated with the extract (30,100, and 300 mg/kg) from postnatal day 35 to the end of the experiment, and underwent behavioral testing to evaluate locomotion, repetitive, and stereotyped movements, anxiety, and social and cognitive behaviors. After behavioral testing, the blood sample was taken from the left ventricle to determine serum catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (TAC). Then the animals were euthanized and their brains were taken out for histological assays of the prefrontal cortex (PFC) and CA1 hippocampus with hematoxylin/eosin. The total phenol and flavonoid content and antioxidant activity of the extract were also measured. A significant improvement was observed in behavioral disturbances, particularly with 300 mg/kg of Passiflora. Moreover, the formation of oxidative stress markers significantly decreased at this dose. The extract also reduced the percentage of damaged cells in the CA1 and PFC. The results indicated that Passiflora extract could ameliorate VPA-induced behavioral aberrations possibly due to the antioxidant actions of its bioactive compounds.

Agmatine improves liver function, balance performance, and neuronal damage in a hepatic encephalopathy induced by bile duct ligation.

INTRODUCTION: In the current study, we investigate whether oral administration of agmatine (AGM) could effectively reduce motor and cognitive deficits induced by bile duct ligation (BDL) in an animal model of hepatic encephalopathy (HE) through neuroprotective mechanisms. METHODS: The Wistar rats were divided into four groups: sham, BDL, BDL+ 40 mg/kg AGM, and BDL+ 80 mg/kg AGM. The BDL rats were treated with AGM from 2 weeks after the surgery for 4 consecutive weeks. The open field, rotarod, and wire grip tests were used to assess motor function and muscle strength. The novel object recognition test (NOR) was performed to evaluate learning and memory. Finally, blood samples were collected for the analysis of the liver markers, the animals were sacrificed, and brain tissues were removed; the CA1 regions of the hippocampus and cerebellum were processed to identify apoptosis and neuronal damage rate using caspase-3 immunocytochemistry and Nissl staining. RESULTS: The serological assay results showed that BDL severely impaired the function of the liver. Based on histochemical findings, BDL increased the neuronal damage in CA1 and Purkinje cells, whereas apoptosis was significantly observed only in the cerebellum. AGM treatment prevented the increase of serum liver enzymes, balance deficits, and neuronal damage in the brain areas. Apoptosis partially decreased by AGM, and there were no differences in the performance of animals in different groups in the NOR. CONCLUSIONS: The study suggests AGM as a potential treatment candidate for HE because of its neuroprotective properties and/or its direct effects on liver function.

Astrocyte responses to postnatal erythropoietin and nano-erythropoietin treatments in a valproic acid-induced animal model of autism.

BACKGROUND: Despite ample evidence of the potential protective effects of erythropoietin (EPO) on the developing brain, no study has addressed the effects of postnatal EPO on behaviors and brain tissue of animal models of autism. In the present study, we examined the therapeutic effects of postnatal erythropoietin on stereotypic behaviors and astrocyte responses via glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) immunohistochemistry in a valproic acid (VPA) animal model of autism. Also, we compared the effects of EPO with EPO-loaded solid lipid nanoparticles (NEPO) because the blood-brain barrier has limited permeability to EPO. METHODS: Pregnant rats received a single dose of VPA (600 mg/kg) at gestational day 12.5. EPO (2000 U/kg) and EPO-loaded solid lipid nanoparticles (NEPO1000 and 2000 U/kg) were injected intraperitoneally from postnatal days 1-5. Repetitive behaviors in male offspring were assessed by a marble burying test. The immune-staining method was performed to evaluate S100B and GFAP-positive cells in the prefrontal cortex and hippocampal CA1 region. RESULTS: VPA animal models revealed more repetitive behavior and displayed higher astrogliosis in the prefrontal cortex (PFC) and hippocampus (CA1) regions. The repetitive behaviors were ameliorated relatively in VPA groups with NEPO2000 treatment, and astrogliosis was reduced even when VPA rats were treated with a lower dosage of NEPO. CONCLUSION: Our results indicate beneficial effects of postnatal NEPO exposure in the VPA animal model of autism, which proposes it as an early treatment in infants with, or at risk of, autism.

The effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

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.

The effects of neurosteroid allopregnanolone on synaptic dysfunction in the hippocampus in experimental parkinsonism rats: An electrophysiological and molecular study.

The dopaminergic system is a powerful candidate targeted for changes of synaptic plasticity in the hippocampus. Higher incidence of Parkinson's disease (PD) in men than women indicates the influence of sex hormones on the PD development. Previous studies have shown that neurodegenerative diseases such as PD are related to the decline of Allopregnanolon (Allo), a metabolite of progesterone; it is also well known that learning and memory are influenced by oscillations in steroidal hormones. Although abnormalities in hippocampal plasticity have been observed in the toxic models of PD, effects of Allo on hippocampal LTP and hippocampal synaptic protein levels, which play an important role in maintaining the integrity of neural connections, have never been analyzed thus far. Experimental groups subjected to the long-term potentiation (LTP) were studied in the CA1 area of the hippocampus. In addition, the levels of hippocampal postsynaptic density protein 95 (PSD-95), neurexin-1 (Nrxn1) and neuroligin (Nlgn) as synaptic molecular components were determined by immunoblotting. Although dopamine denervation did not alter basal synaptic transmission and pair-pulse facilitation of field excitatory postsynaptic potentials (fEPSPs), the induction and maintenance of LTP were impaired in the CA1 region. In addition, the levels of PSD-95, Nrxn1 and Nlgn were significantly decreased in the hippocampus of 6-OHDA-treated animals. Such abnormalities in synaptic electrophysiological aspects and protein levels were abolished by the treatment with Allo. These findings showed that partial dopamine depletion led to unusual synaptic plasticity in the CA1 as well as the decrease in synaptic proteins in the hippocampus. Our results demonstrated that Allo ameliorated these deficits and preserved pre- and post-synaptic proteins. Therefore, Allo may be an effective factor in maintaining synaptic integrity in the mesolimbic pathway.

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.

Effects of psychological or physical prenatal stress on attention and locomotion in juvenile rats.

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exposure to the physical or psychological stress on locomotion and attention were evaluated by using open field test (OFT) and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In addition, the level of corticosterone was measured after the ASR trial.Results: Male and female rodents that underwent prenatal physical and psychological stress had an augmented velocity in OFT, and only male animals showed an increased ASR. Neither male nor female offsprings had an alteration in the level of corticosterone and PPI values regardless of the stress type.Conclusion: Our results revealed that exposure to stress during the development of fetus increases ASR in a sex-dependent manner. This finding might implicate the effect of prenatal stress on attention in male offspring regardless of the stress type.

Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats.

INTRODUCTION: The present study was designed to clarify the effects of resveratrol (RSV) on social behavioral alterations and nociceptive reactivity in valproic acid (VPA)-induced autistic-like model in female and male rats. METHODS: Pregnant Wistar rats were randomly divided in five groups. Animals received saline, DMSO, VPA, RSV and RSV + VPA. VPA was administered (600 mg/kg, i. p.) on embryonic day 12.5 (E12.5) and pretreatment by resveratrol (3.6 mg/kg, s. c.) was applied on E6.5 until E18.5. All offspring were weaned on postnatal day 21 and the experiments were done in male and female rats on day 60. Social interaction, hot plate and tail flick tests were set out to assess social deficits and pain threshold, respectively. Sociability index (SI), Social novelty index (SNI) and latency time were calculated as the standard indices of social behaviors and pain threshold, respectively. RESULTS: The results indicated that systemic intraperitoneal administration of VPA (600 mg/kg) significantly decreased SI and SNI in social interaction test (SIT) especially in male rats, indicating the social impairments caused by VPA. RSV (3.6 mg/kg, s. c.) reversed VPA-induced social deficits in male rats, but not in female group. VPA administration resulted in significant increase in latency time in the hot plate and tail flick tests in male rats, whereas it had no such dramatic effect in females. RSV administration in combination with VPA had no significant effect on latency time compared to the valproic acid group in male rats. It is important to note that RSV by itself had no significant effect on SI, SNI and latency time in female and male rats. CONCLUSION: It can be concluded that valproic acid produces autistic-like behaviors and increases pain threshold in male rats which may be ameliorated at least in part by resveratrol administration. Further studies are needed to elucidate the molecular mechanisms involved in valproic acid and resveratrol-induced effects.

Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines.

Aging causes changes in body composition and energy balance. Estrogen plays an important role in body's metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19-21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

Ibuprofen Protection Against Restrained Chronic Stress-induced Depression in Male Rats.

INTRODUCTION: Stress predisposes organisms to depression and cognitive impairments, and seems to interact with metabolic homeostasis. The inflammatory response and the upregulation of proinflammatory cytokines are some of the consequences related to chronic stress. In this study, we investigated the preventive effect of chronic administration of ibuprofen, as an inhibitor of cyclooxygenases, on the cognitive and behavioral alterations and the weight gain reduction induced by simultaneous chronic restraint stress in rats. MATERIALS AND METHODS: Male Wistar rats were subjected to chronic restraint stress and injected daily with the variable doses of ibuprofen or vehicle, for 21 consecutive days. Then, all animals were tested with the forced swim test and passive avoidance conditioning. Also, the weight of the animals was recorded before and after the interventions. Ultimately, plasma interleukin 6 (IL-6) levels were measured. RESULTS: Chronic stress increased depressive-like behaviors, impaired learning, and disrupted the normal weight gain. However, the animals that received the highest dose of ibuprofen showed less depressive-like behaviors, a better avoidance memory, and a higher weight gain. However, the level of plasma IL-6 did not differ significantly between the study groups. CONCLUSION: The administration of ibuprofen prevents the cognitive and behavioral consequences of chronic stress. During the recovery, the plasma levels of IL-6 were not elevated by stress, and the IL-6 levels did not predict the behavioral performance of the stressed animals. The exact mechanisms of the protective effects of ibuprofen against chronic stress need to be further investigated.

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.

Novel object recognition memory in REM sleep-deprived rats: Role of the cannabinoid CB1 receptor.

A survey of the literature indicates that both rapid eye movement sleep deprivation (RSD) and activation of cannabinoid CB1 receptor (CB1R) may impair novel object recognition (NOR) memory in rodents. To our knowledge, so far, no previous study has investigated the probable effects of RSD on the different phases of NOR memory. Moreover, far too little attention has been paid to the potential role of the CB1R in the effects of RSD on object memory. Therefore, the major objective of this study was to investigate the probable role of the CB1R in the acquisition, consolidation, retrieval, and reconsolidation of NOR memory in the RSD rats. A 12-h paradigm of RSD using the multiple platform method did not affect acquisition, but it impaired the consolidation, retrieval, and reconsolidation of NOR memory. Administration of the CB1R antagonist rimonabant (1 or 3 mg/kg, i.p.) did not have significant effects on the acquisition and reconsolidation, but it improved RSD-induced impairment of the consolidation and retrieval of object memory, especially at the dose of 3 mg/kg. In addition, the RSD paradigm did not affect the levels of plasma corticosterone as an important marker of stress in rat. The results revealed that RSD may have different effects on the different phases of NOR memory which may not be attributable to the effects of stress. Our findings would seem to suggest that the CB1R can be targeted to, at least partially, modulate the adverse effects of RSD on the process of NOR memory.

Ameliorating effects of berberine on MK-801-induced cognitive and motor impairments in a neonatal rat model of schizophrenia.

Neonatal administration of MK-801 (NMDA receptor antagonist) results in schizophrenia-like behaviors in rodents. Berberine (BBR) is a herbal alkaloid, which shows many neuroprotective properties in neurodegenerative diseases. The present study was designed to clarify whether systemic administration of BBR improves motor and cognitive disturbances induced by MK-801 treatment. Male Wistar rat pups were treated with intraperitoneal administration of saline (1 ml/kg) as a control group, MK-801 (1 mg/kg), BBR (20 mg/kg) and BBR (20 mg/kg) plus MK- 801 (1 mg/kg). Treatments were administered on postnatal day (P) 6-10 for once daily. To assess motor learning, coordination as well as spatial learning and memory, behavioral evaluation was performed at P55-60, using the rotarod, open field, and Morris water maze paradigm. MK-801 injection led to motor perturbations in both the open field and accelerating rotarod tests, which were restored by BBR. Also, BBR improved learning impairments, although it had no significant effect on the Probe test. Taken together, it can be concluded that BBR produces a neuroprotective effect in rats with MK-801-associated behavioral deficits. Given that the MK-801 exposure demonstrates an animal model of schizophrenia, we suggest that timely BBR administration may act as a potential treatment in schizophrenic patients.

Behavioral consequences of simultaneous postnatal exposure to MK-801 and static magnetic field in male Wistar rats.

Various experimental studies reported some neurobehavioral adverse effects of static magnetic field (SMF) exposure. The reason is unclear, but one of the possibilities might be alternations in the level of the neurotransmitters and their receptors. Considering the critical role of N-Methyl D-aspartate (NMDA) receptors in the molecular regulation of cognition, motor control, and synaptic plasticity, it is important to investigate interactions between SMF exposure and administration of NMDA receptor blockers such as MK-801. Now, we administered low-dose (0.1 mg/kg) MK-801 to the male Wistar rats, from postnatal day (P) 6 to 10 and investigate whether its effects change under the influence of SMF exposure. Morris water maze, open field test, rotarod, and elevated plus maze tests were performed on P60-63 to evaluate long-term effects on learning and memory, locomotion activities, and anxiety-like behaviors. Our results showed that administration of low-dose MK-801 did not lead to significant adverse effects on their long-term anxiety-like behaviors, locomotion, learning, and memory; however, simultaneous exposure to SMF can result in these adverse effects. In conclusion, exposure to SMF can augment the neurobehavioral effects of MK-801, by enhancing the blockage of the NMDA receptors. Further studies are required to confirm these results.

Early enriched environment prevents cognitive impairment in an animal model of schizophrenia induced by MK-801: Role of hippocampal BDNF.

Early life experience has long-lasting effects on brain and behaviour. This study aims to investigate the long-term effects of enriched environment (EE), which was imposed during the animals' development, on their recognition memory as well as hippocampal levels of brain-derived neurotrophic factor (BDNF), in an animal model of schizophrenia induced by chronic postnatal administration of MK-801. Forty male and female rat pups were separated in four distinct groups for each sex (n = 10). The rats were injected with MK-801 (1 mg/kg) or saline (1 cc/kg) on their postnatal days (P) 6-10. MK-801 and Control rats were maintained in standard or enriched cages (containing toys, tunnels, running wheels, and climbing frame), from their birth up to the time of behavioral experiments at P60. Neonatal challenge with MK-801 significantly impaired novel object recognition (NOR) in both male and female animals. EE exposure reversed the recognition memory only in male rats. MK-801 resulted in decreased levels of BDNF in the hippocampus, and EE exposure restored the decreased level. Our results provide evidence that BDNF plays an important role in pathophysiology of schizophrenia in the present animal model, and is a possible mechanism through which early EE can enhance the cognitive functions.