Maternal Substance Use and Early-Life Adversity: Inducing Drug Dependence in Offspring, Interactions, Mechanisms, and Treatments.

The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring>s genders and rewire the brain>s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.

Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 µg/µl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Transmission of behavioral and cognitive impairments across generations in rats subjected to prenatal valproic acid exposure.

BACKGROUND: Autism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations. OBJECTIVES: The primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development. METHODS: In this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks. RESULTS: Our data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety-like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic-like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission. CONCLUSION: In summary, our findings underscore the transmission of autistic-like behaviors, including anxiety-like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex.

Anodal HD-tDCS on the dominant anterior temporal lobe and dorsolateral prefrontal cortex: clinical results in patients with mild cognitive impairment.

OBJECTIVES: Mild cognitive impairment (MCI) is a neurocognitive disorder in which the cognitive and mental abilities of humans are declined. Transcranial direct-current stimulation (tDCS) is an emerging noninvasive brain stimulation technique aimed at neuromodulation. In this study, we investigate whether high-definition anodal tDCS stimulation (anodal HD-tDCS) in MCI patients in two different brain regions will be effective in improving cognitive function. METHODS: This study was done as a randomized, double-blind clinical trial. Sixty MCI patients (clinically diagnosed by expert neurologists) were randomly divided into three groups. Two groups received 2-mA anodal HD-tDCS for 20 min for 2 weeks (5 consecutive days in each week, 10 days in total). In the first group (twenty patients), the left dorsolateral prefrontal cortex (left DLPFC) was targeted. In the second group (twenty patients), the target zone was the dominant anterior temporal lobe (DATL). The third group (twenty patients) formed the Sham group. The Montreal Cognitive Assessment (MoCA) and Quality of Life in Alzheimer's Disease (QoLAD) were considered as the outcome measures. RESULTS: MCI patients obtained the highest MoCA mean scores in both left DLPFC and DATL groups versus the study baseline 2 weeks after the intervention. In addition, the MoCA mean scores of MCI patients were greater in both intervention groups compared to the Sham group up to 3 months post-stimulation (p-value ≤ 0.05). However, as we moved away from the first stimulation day, a decreasing trend in the MoCA mean scores was observed. Moreover, in the left DLPFC and DATL groups, higher QoLAD mean scores were observed 3-month post-stimulation, highlighting the effectiveness of anodal HD-tDCS in improving the quality of life in MCI patients. CONCLUSION: In this research, it was shown that applying anodal HD-tDCS at left DLPFC and DATL brain regains for two successive weeks improves cognitive function in MCI patients (by obtaining higher values of MoCA scores) up to 3 months after the intervention compared to the Sham group. This illustrates the positive effects of HD-tDCS, as a non-pharmacological intervention, for improving cognitive function and quality of life in MCI patients. SIGNIFICANCE: Two weeks after anodal HD-tDCS of the DLPFC and DATL brain regions, the MCI patients achieved the highest MoCA mean scores compared to the Sham group across all measurement intervals.

Effects of music on cognitive behavioral impairments in both sex of adult rats exposed prenatally to valproic acid.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive behaviors and interests. In previous studies, music has been identified as an intervention therapy for children with ASD. OBJECTIVES: The present study evaluated the effects of music on cognitive behavioral impairments in both sexes of adult rats exposed prenatally to Valproic acid. METHODS: For induction of autism, pregnant female rats were pretreated with either saline or VPA (600 mg/kg.i.p.) at gestational day (GD) 12.5. Male and female offspring were divided into Saline.Non-Music, VPA.Non-Music, Saline.Music, and VPA.Music groups. The adult rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 60 to 90. Social interaction and Morris water maze (MWM) tasks were tested at PND 90. RESULTS: Our results revealed that prenatal exposure to VPA decreased sociability and social memory performance in both sexes of adult rats. Moreover, prenatal exposure to VPA created learning and memory impairments in both sexes of adult rats in the MWM task. Music intervention improved sociability in both sexes of VPA-exposed rats and social memory in both sexes of VPA-exposed rats, especially in females. Furthermore, our results revealed that music ameliorated learning impairments in VPA-exposed female rats in the MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes, especially in females, which needs more investigation in molecular and histological fields in future studies. CONCLUSION: Music intervention improved sociability and social memory in adult VPA-exposed rats, especially in female animals. Furthermore, music improved memory impairments in VPA-exposed rats of both sexes. It seems that music had a better influence on female rats. However, future studies need more investigations in molecular and histological fields.

Aggravation of cognitive impairments in the valproic acid-induced animal model of autism in BALB/c mice infected with Toxoplasma gondii.

PURPOSE: Toxoplasmosis is a disease caused by infection with a type of coccidial protozoan parasite called Toxoplasma gondii. The relationship between toxoplasmosis and cognitive disorders in neurodegenerative diseases has been proven. There is also evidence that children born to Toxoplasma-infected mothers are more likely to develop autism. METHODS: In the present study, Toxoplasma-infected pregnant BALB/c mice were given valproic acid to induce autism in their male offspring, and their social behaviors, learning, and memory were examined. Chronic toxoplasmosis was established in BALB/c mice by intraperitoneal injection of cyst form of T. gondii. To induce autism, 600 mg/kg of valproic acid was injected intraperitoneally into mice on the 12.5th day of pregnancy. The behavioral experiments, such as social interaction, novel object recognition, and passive avoidance tasks, were performed on male offspring at 50 days. RESULTS: Toxoplasma and valproic acid during the embryonic period caused social communication deficits and disrupted recognition memory and avoidance memory in offspring. Our findings showed that administering valproic acid to Toxoplasma-infected mothers exacerbates cognitive disorders in their offspring.

Impact of Sleep Deprivation on the Brain's Inflammatory Response Triggered by Lipopolysaccharide and Its Consequences on Spatial Learning and Memory and Long-Term Potentiation in Male Rats.

INTRODUCTION: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain's inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. METHODS: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1ß (IL-1ß) levels were significantly higher in the LPS1+SD group than in the Saline group. CONCLUSION: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone.

Myrtenol Inhalation Mitigates Asthma-Induced Cognitive Impairments: an Electrophysiological, Behavioral, Histological, and Molecular Study.

Asthma is an inflammatory disorder with significant health problems. It generally affects the lungs but can also impact brain performance via several mechanisms. Some investigations have proposed that asthma impairs cognition. This study assessed the impacts of myrtenol as a monoterpene on cognitive disorders following asthma at behavioral, molecular, and synaptic levels. Asthma was induced by injection and inhalation of ovalbumin (OVA). Male Wistar rats were allocated to five groups: control, asthma, asthma/vehicle, asthma/myrtenol, and asthma/budesonide. Myrtenol (8 mg/kg) or budesonide (160 µg/kg) was administered through inhalation once a day for 1 week, and at the end of the inhalation period, behavioral tests (MWM and Open Field), field potential recording, hippocampal brain-derived neurotrophic factor (BDNF), IL1ß (ELISA), and NFκB measurement (Western blot) were performed to evaluate cognitive performance. Moreover, H&E (hematoxylin and eosin) staining was used for hippocampus histological evaluation. Myrtenol improved spatial learning, memory, LTP (long-term potentiation) impairments, and anxiety-like behaviors following asthma. Myrtenol inhalation increased the BDNF level and decreased the IL1ß level and NFκB expression in the hippocampus of the asthmatic rats. The neuronal damage in the hippocampus following allergic asthma was alleviated via myrtenol administration. Myrtenol, as an herbal extract, protects the hippocampus from asthma consequences. Our observations revealed that myrtenol can improve spatial learning, memory, synaptic plasticity impairments, and anxiety-like behaviors following asthma. We believe that these ameliorating effects of myrtenol can be attributed to inflammation suppression and increased BDNF in the hippocampus.

Chronic maternal morphine exposure and early-life adversity induce impairment in synaptic plasticity of adolescent male rats.

Maternal morphine exposure has negative consequences for learning and memory in the offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal Separation (MS) can cause behavioral and neuropsychiatric problems later in life. It seems that adolescents are more susceptible to the effects of early life stress; evidence for the combinatory effects of oral chronic maternal morphine exposure and MS in the CA1 area of the hippocampus in the male adolescent offspring is not found. Therefore, this study aimed to evaluate the effects of chronic maternal morphine consumption (21 days before and after mating, and gestation), and MS (180 min/day from postnatal day (PND) 1-21) on the synaptic plasticity of male offspring in mid-adolescence. Control, MS, Vehicle (V), Morphine, V + MS, and Morphine + MS groups were tested for in vivo field potential recording from the CA1 area of the hippocampus. The current results demonstrated that chronic maternal morphine exposure impaired the induction of early long-term potentiation (LTP). MS impaired average fEPSPs, induction of early-LTP and maintenance. Chronic maternal morphine exposure in combination with MS impaired the induction of early LTP but didn't deteriorate maintenance and the average field excitatory post-synaptic potentials (fEPSPs) measured in two hours. Prepulse facilitation ratios remained undisturbed and I/O curves showed decreased fEPSP slopes at high stimulus intensities in combinatory group. We concluded that chronic maternal morphine exposure in combination with MS negatively affects synaptic plasticity in the CA1 area in male adolescent offspring.

Exploring the potential of a novel phenoxyethyl piperidine derivative with cholinesterase inhibitory properties as a treatment for dementia: Insights from STZ animal model of dementia.

Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.

Naringenin mitigates reserpine-induced anxiety-like behavior, neurodegeneration, and oxidative stress in male rats.

Reserpine (Res) induces anxiety-like behaviors, orofacial dyskinesia, and neurodegeneration in animals, the pathophysiology of which has been related to oxidative stress. The purpose of this study was to investigate whether naringenin (NG) could prevent reserpine-induced anxiety-like behaviors, orofacial dyskinesia, and neurodegeneration in male rats. Twenty-eight male rats were distributed into different groups as follows: Control rats; vehicle rats, which received the vehicles (normal saline, orally; acetic acid, intraperitoneally); Res rats (1 mg/kg/day) every other day for 3 days; and Res + NG rats, which received NG (50 mg/kg, orally, pre-treatment for 7 days), followed by Res. Administration of Res significantly increased chewing frequency compared with the control group (P < 0.01) and NG reversed the effect of Res on this factor (P < 0.05). Res induced an anxiety-like behavior in rats in the plus maze, and pre-treatment with NG improved this behavior. In addition, Res significantly increased the level of oxidative stress markers and degenerated neurons in the striatum; NG was able to ameliorate these damages. The results of this study demonstrated that Res caused behavioral disorders and increased the levels of oxidative stress in male rats; the use of NG was effective in treating these disorders. Therefore, NG should be considered as a preventive agent for reserpine-induced brain damage in male rats.

Amelioration of cognition impairments in the valproic acid-induced animal model of autism by ciproxifan, a histamine H3-receptor antagonist.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behavior. Many studies show that the number of cognitive impairmentscan be reduced by antagonists of the histamine H3 receptor (H3R). In this study, the effects of ciproxifan (CPX) (1 and 3 mg/kg, intraperitoneally) on cognitive impairments in rat pups exposed to valproic acid (VPA) (600 mg/kg, intraperitoneally) wereexamined on postnatal day 48-50 (PND 48-50) using marble-burying task (MBT), open field, novel object recognition (NOR), and Passive avoidance tasks. Famotidine (FAM) (10, 20, and 40 mg/kg, intraperitoneally) was also used to determine whether histaminergic neurotransmission exerts its procognitive effects via H2 receptors (H2Rs). Furthermore, a histological investigation was conducted to assess the degree of degeneration of hippocampal neurons. The results revealed that repetitive behaviors increased in VPA-exposed rat offspring in the MBT. In addition, VPA-exposed rat offspring exhibited more anxiety-like behaviors in the open field than saline-treated rats. It was found that VPA-exposed rat offspring showed memory deficits in NOR and Passive avoidance tasks. Our results indicated that 3 mg/kg CPX improved cognitive impairments induced by VPA, while 20 mg/kg FAM attenuated them. We concluded that 3 mg/kg CPX improved VPA-induced cognitive impairments through H3Rs. The histological assessment showed that the number of CA1 neurons decreased in the VPA-exposed rat offspring compared to the saline-exposed rat offspring, but this decrease was not significant. The histological assessment also revealed no significant differences in CA1 neurons in VPA-exposed rat offspring compared to saline-exposed rat offspring. However, CPX3 increased the number of CA1 neurons in the VPA + CPX3 group compared to the VPA + Saline group, but this increase was not significant. This study showed that rats prenatally exposed to VPA exhibit cognitive impairments in the MBT, open field, NOR, and Passive avoidance tests, which are ameliorated by CPX treatment on PND 48-50. In addition, morphological investigations showed that VPA treatment did not lead to neuronal degeneration in the CA1 subfield of the hippocampus in rat pups.

Music alleviates cognitive impairments in an animal model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairment in social communication and restrictive and repetitive behaviors and interests. Music has emerged in the past decade as an intervention therapy for children with ASD. The aim of the present study was to evaluate the effects of music on cognition impairments in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism on embryonic day 12.5 (E12.5) (600 mg/kg). Male and female pups were sub divided into four main groups (Saline.Non-music, VPA.Non-music, Saline.Music, and VPA.Music). The rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 21 to 50. Autistic-like behaviors were tested using a social interaction, the Morris water maze (MWM), and a passive avoidance tasks at the end of the PND 50. Our results demonstrated that VPA-exposed rat pups had significantly lower sociability and social memory performance compared with the saline-exposed rats in both sexes. VPA-exposed rat pups exhibited learning and memory impairments in the MWM and passive avoidance tasks. Our results demonstrated that music improved sociability in VPA-exposed rats, especially in males. Furthermore, our findings revealed that music improved learning impairments in VPA-exposed male rats in MWM task. In addition, music improved spatial memory impairments in VPA-exposed rats of both sexes. We also found that music improved passive avoidance memory impairments in VPA-exposed rats of both sexes, especially in females. More investigation in future studies are needed.

Impact of ketamine administration on chronic unpredictable stress-induced rat model of depression during extremely low-frequency electromagnetic field exposure: Behavioral, histological and molecular study.

OBJECTIVES: In the study, we examined the effects of ketamine and extremely low-frequency electromagnetic fields (ELF-EMF) on depression-like behavior, learning and memory, expression of GFAP, caspase-3, p53, BDNF, and NMDA receptor in animals subjected to chronic unpredictable stress (CUS). METHODS: After applying 21 days of chronic unpredictable stress, male rats received intraperitoneal (IP) of ketamine (5 mg/kg) and then were exposed to ELF-EMF (10-Hz, 10-mT exposure conditions) for 3 days (3 h per day) and behavioral assessments were performed 24 h after the treatments. Instantly after the last behavioral test, the brain was extracted for Nissl staining, immunohistochemistry, and real-time PCR analyses. Immunohistochemistry (IHC) was conducted to assess the effect of ketamine and ELF-EMF on the expression of astrocyte marker (glial fibrillary acidic protein, GFAP) in the CA1 area of the hippocampus and medial prefrontal cortex (mPFC). Also, real-time PCR analyses were used to investigate the impacts of the combination of ketamine and ELF-EMF on the expression of caspase3, p53, BDNF, and NMDA receptors in the hippocampus in rats submitted to the CUS procedure. Results were considered statistically significant when p < .05. RESULTS: Our results revealed that the combination of ketamine and ELF-EMF increased depression-like behavior, increased degenerated neurons and decreased the number of GFAP (+) cells in the CA1 area and mPFC, incremented the expression of caspase-3, and reduced the expression of BDNF in the hippocampus but showed no effect on the expression of p53 and NMDA-R. CONCLUSIONS: These results reveal that combining ketamine and ELF-EMF has adverse effects on animals under chronic unpredictable stress (CUS).

Chronic morphine exposure and maternal separation induce impairments in cognition and locomotor activity of male adolescent rats.

Maternal morphine exposure reduces motivation for basic cognitive tasks, followed by executive function deficits in attention and accuracy. It also induces depression-like behaviors and has negative consequences for learning and memory in offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal separation (MS) can originate behavioral and neuropsychiatric abnormalities later in life. It seems that adolescents are more susceptible to the effects of early-life stress; Therefore, this study aimed to evaluate the effects of chronic morphine consumption (21 days before and after mating and gestation) and MS (180 min/day from postnatal day [PND] 1-21) on the cognitive and behavioral performance of male offspring in mid-adolescence. Six groups, including control, MS, V (vehicle), morphine, V+MS, and morphine+MS, were tested for open field (OF), novel object recognition (NOR), and the Morris water maze (MWM). The results of the OF test showed that MS increased locomotor activity and movement velocity. Inner and outer zone durations did not differ among groups. The body stretching of the morphine+MS rats was significantly more than the MS rats. Moreover, the MS and morphine+MS groups showed significantly less sniffing behavior in the OF test. The MS group showed deficits in spatial learning in the MWM test, but recognition memory in the NOR and spatial memory in the MWM tests were not significantly different among groups. We concluded that MS could induce impairments in spatial learning and locomotor activity that could be worsened by maternal morphine exposure in adolescent male rats.

Investigating the effects of Citrullus colocynthis on cognitive performance and anxiety-like behaviors in STZ-induced diabetic rats.

Background: Diabetes can impair cognitive performance and lead to dementia. Patients with type 1 diabetes mellitus (T1DM) are reported with different levels of cognitive dysfunctions in various cognitive domains ranging from general intellectual testing to specific deficits with visuospatial abilities, motor speed, writing, attention, reading, and psychomotor efficiency. The present study aimed to investigate the effect of Citrullus colocynthis on cognitive functions.Methods: A total of 42 male Wistar rats (3-4 months old and weighing 200-250 g) were tested in the current study. Rats were randomly allocated into 3 groups of control, Diabetes, and Diabetes + Drug. The diabetic rats received Citrullus colocynthis extraction orally. The behavioral tests included the open field, elevated plus maze (EPM), novel object recognition (NOR), passive avoidance tests, and Morris Water Maze (MWM) tests. Data were analyzed using student and paired t-tests via SPSS software version 16.Results: Our results showed the protective effects of Citrullus colocynthis administration against cognitive impairments. This is followed by STZ-induced diabetes in the MWM, novel object recognition, and passive avoidance tasks. Also, it was found that Citrullus colocynthis improved anxiety in diabetic rats.Conclusion According to the findings of this study, the administration of 200 mg/kg C. colocynthis once per day for 40 days can lead to ameliorated cognitive impairments and antidiabetic effects such as increasing body weight and decreasing FBS.

The effect of gallic acid on memory and anxiety-like behaviors in rats with bile duct ligation-induced hepatic encephalopathy: Role of AMPK pathway.

Objective: Hepatic encephalopathy (HE) is a serious neurological syndrome which is caused by acute and chronic liver diseases. In this study, the effect of gallic acid (GA) as an activator of AMP-activated protein kinase (AMPK) on memory and anxiety-like behaviors in rats with HE caused by bile duct ligation (BDL) was investigated. Materials and Methods: The rats were randomly divided into the following eight groups (n=7): sham; BDL; BDL+GA 20 mg/kg; BDL+GA 30 mg/kg; sham+dorsomorphin or compound C (CC) (as AMPK inhibitors); BDL+CC; BDL+GA 20 mg/kg+CC; and BDL+GA 30 mg/kg+CC. The rats received GA once daily by gavage for four weeks, and dorsomorphin 6.2 µg per rat was administered on a daily basis via bilateral intraventricular injection for four weeks. Behavioral tests including novel object recognition (NOR), open field and Morris water maze (MWM) were used to evaluate anxiety and memory in the rats. Results: Examining some parameters of NOR and MWM tests showed that memory performance was significantly reduced in the BDL versus the sham group, and in the BDL+CC versus the sham+CC group (p<0.05). GA intake improved memory in the GA-receiving groups compared with the BDL and BDL+CC groups (p<0.05). Examining some parameters of open field test showed that anxiety was significantly increased in the BDL versus the sham group, and the BDL+CC versus the sham+CC group (p<0.05). GA intake reduced anxiety in GA-receiving groups compared with the BDL+BDL+CC group (p<0.05). Conclusion: GA was effective in improving cognitive and anxiety-like behaviors through activating AMPK.

The effects of combined resveratrol and high intensity interval training on the hippocampus in aged male rats: An investigation into some signaling pathways related to mitochondria.

Objectives: High-intensity interval training (HIIT) is a shape of interval training that provides ameliorated athletic capacity and has a good effect on health. Resveratrol is a natural polyphenol abundant in grapes and red wine and has been demonstrated to apply various useful health impacts on the body. This research aimed to evaluate the interactive effects of swimming HIIT and resveratrol consumption on SIRTs 3 & 4, NAD+/NADH, AMPK and SOD2 expression in aged rats. Materials and Methods: In total, forty-five old male albino rats (Wistar) with the age of twenty months were allocated into 5 groups randomly. Control group (Ctrl), Swimming HIIT group (Ex: Exercise), Swimming HIIT with Resveratrol consumption group (R+Ex), Resveratrol consumption group (R) and solvent of resveratrol consumption group (vehicle). R+Ex group accomplished the exercise and consumed resveratrol (10 mg/kg/day, gavage) for 6 weeks. Results: HIIT & resveratrol significantly increased NAD+/NADH, SOD 2 and AMPK in the aged rats. HIIT increased SIRT3, but resveratrol reduced it. As for SIRT4, HIIT decreased it, while resveratrol positively affected it. Conclusion: Resveratrol and HIIT, especially their combination, have anti-oxidant and anti-aging effects on the hippocampus of old rats.

Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism.

RATIONALE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and cognitive behaviors. Histamine H3 receptor (H3R) antagonists are considered as therapeutic factors for treating cognitive impairments. OBJECTIVES: The aim of the present study was to evaluate the effects of the H3R antagonist, ciproxifan (CPX), on cognition impairment especially, spatial learning memory, and synaptic plasticity in the CA1 region of the hippocampus in autistic rats. METHODS: Pregnant rats were injected with either valproic acid (VPA) (600 mg/kg, i.p.) or saline on an embryonic day 12.5 (E12.5). The effects of the H3R antagonist, ciproxifan (CPX) (1, 3 mg/kg, i.p.), were investigated on learning and memory in VPA-exposed rat pups and saline-exposed rat pups using Morris water maze (MWM) and social interaction tasks. The H2R antagonist, famotidine (FAM) (10, 20, 40 mg/kg, i.p.), was used to determine whether brain histaminergic neurotransmission exerted its procognitive effects through the H2R. In addition, synaptic reinforcement was evaluated by in vivo field potential recording. RESULTS: The results showed that VPA-exposed rat pups had significantly lower sociability and social memory performance compared to the saline rats. VPA-exposed rat pups exhibited learning and memory impairments in the MWM task. In addition, VPA caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results demonstrated that CPX 3 mg/kg improved VPA-induced cognitive impairments and FAM 20 mg/kg attenuated cognitive behaviors as well as electrophysiological properties. CONCLUSIONS: CPX 3 mg/kg improved VPA-induced impairments of LTP as well as learning and memory deficits through H2R.

Promising Effects of Naringenin and Melatonin against Hepatic Encephalopathy Impairments Induced by Bile Duct Ligation in Male Rats.

BACKGROUND: Bile duct ligation (BDL) is used for evaluating the protective effects of different agents with anti-inflammatory and antioxidant properties against the liver and brain damages. Naringenin (N) and melatonin (M) are used as protectants in various models of diseases. AIMS: In the current research, the combinational effects of these well-known anti-inflammatory and antioxidants agents were investigated against cerebral injuries induced by BDL in male rats. METHODS: The animals were distributed into the following groups: Sham, BDL + Vehicle and BDL+ N + M. Neuronal damages were evaluated using biochemical, motor behavioral tasks and morphological assessments. RESULTS: Based on the data, BDL resulted in decreasing locomotor activity, which was reversed by N and M. Morphological study confirmed that BDL led to neurodegeneration in the cortex of the rats, and the N and M treatment preserved cortical neurons. In addition, immunohistochemical (IHC) study of the rat cortex showed that BDL resulted in increasing the activated astrocytes, and the N and M treatment reduced the number of activated cells. CONCLUSION: These results obviously depicted combinational therapy with N and M to exert positive effects in the BDL rats, probably due to their synergistic anti-inflammatory and antioxidant activities.