Basic and Clinical Neuroscience
Volume:11 Issue: 4, Jul-Aug 2020

N-Methyl-3, 4-methylenedioxyamphetamine (MDMA), or ecstasy is a recreational drug of abuse. It is a synthetic substance that affects the body’s systems, which its mechanism of action and treatment should be more investigated. MDMA provides an immediate enjoyable feeling by stimulating the release of neurotransmitters, such as dopamine and serotonin in the brain. Unfortunately, abnormal regulation of the brain neurotransmitters, as well as the increased oxidative stress causes damage to the brain neurons after the MDMA exposure. Only a few studies have been done regarding its treatment. Thus, the treatment of MDMA complications should be further explored mainly by targeting its mechanism of action in the neurotransmitter systems. Hence, this study presents a short review regarding the recent findings on the role of neurotransmitters to cause MDMA neurotoxicity. The results will be useful for future research in elucidating the potential treatment based on the targeted mechanisms to treat the neurotoxic effects of MDMA.

This research provides an overview of the historical advances of the maze tests that are widely used to assess the cognitive impairments in rodents. Particularly, this study focuses on the issue of learning and memory behavioral tests, including dry and water mazes. Several types of mazes have been used in this setting, but their real advantages and applications depend on the type selected by the researcher. We answered some of the basic questions that any interested researcher in such studies may be faced with. The reviewed topics are as follows: the definition of maze learning, the role of the memory in the maze learning, the differences between several types of mazes, and foremost the rationale behind the maze constructions and designs.

The use of opioids such as morphine has anti-pain effects along with some side effects on body organs. Opioids such as morphine can be transferred from mother to child through the placenta and or breastfeeding. This study aimed to assess the effect of morphine on mineral content and histological changes of incisor teeth of rats born to morphine-addicted mothers.

In this experimental animal study, 24 pregnant rats were randomly divided into 6 groups of control, morphine, zinc, vitamin D, morphine plus zinc, and morphine plus vitamin D. After completion of the breastfeeding period, two babies were randomly selected among the newborns of each mother rat. Mineral content was analyzed using the Rontec device. The obtained data were analyzed by Newman-Keuls multiple comparisons test in Prism 5.

Results showed a significant reduction in fluorine content in the experimental groups compared with the control group (P<0.05). The magnesium content in the experimental groups was significantly higher than that in the control group (P<0.05). Microscopic assessment of the slides showed a significantly less enamel maturation in the experimental groups compared with the control group (P<0.05).

Morphine use by mothers decreased the fluorine content of tooth structure and retarded the maturity of the enamel of infants.

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.

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. 

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.

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.

Psychomotor performance task is used to assess the arousal and cognitive functions of the central nervous system. Alternatively, human visual working memory reflects the capability of the individual’s short-term memory. Psycho-mental stimuli are linked to the stimulation of Malondialdehyde (MDA) formations. Citicoline is a nootropic nucleotide agent with a favorable effect on the augmentation of human memory and cognitive function. Thus, the purpose of this study was to determine the effect of citicoline on human vigilance, visual working memory, and oxidative stress using healthy volunteers. 

40 healthy volunteers were enrolled and divided into two groups: group A: 20 volunteers received 500mg/day starch capsule for two weeks and group B: 20 volunteers received 500mg/day citicoline capsule for two weeks. Human vigilance, visual working memory, and oxidative stress markers of each volunteer were assessed before and after citicoline and placebo intake. The obtained data were analyzed by SPSS regarding P<0.05 as statistically significant.

Placebo had no significant effect on human vigilance and visual working memory after two weeks of therapy (P>0.05), whereas citicoline improved most variables of psychomotor performances and working memory (P<0.01). Placebo significantly increased serum MDA levels from 19.44±2.11 to 29.66±3.28 nmol/mL (P=0.0001), while citicoline significantly decreased MDA serum levels from 19.11±2.66 to 15.63±1.33 nmol/mL (P=0.0001).

Citicoline improves human psychomotor vigilance, arousal, and visual working memory with significant amelioration of oxidative stress compared with placebo.

Methomyl (MET) is a carbamate insecticide, used in agriculture and public health to eliminate harmful insects. Besides its advantages in agriculture, it causes neurotoxic effects. The aim of this study was to evaluate the effect of MET on Spatial Working Memory (SWM), oxidative stress parameters,  and histopathological changes in the hippocampus, as well as the possible protective role of Pelargonium graveolens Essential Oil (EO).

Male Wistar rats were randomized into four groups of six animals: group I as the control that received the vehicle; group II received EO (75 mg/kg b.w), group III received MET (2 mg/kg b.w); and group IV received both MET and EO. The rats were administered the respective doses orally by gavage for 28 days. SWM was assessed using Y-maze on the day before the first treatment and day 28 after the last dose. They were sacrificed by decapitation and their brains were taken for assessing oxidative stress parameters and histopathological analysis.

MET treatment caused SWM deficits. Furthermore, drastic changes were observed  in aspartate transaminase, alanine aminotransferase, and alkaline phosphatase activities. The level of malondialdehyde significantly increased, whereas antioxidant (glutathione-S-transferase and catalase) enzyme activities significantly decreased. The CA1 region of the hippocampus of rats exposed to MET revealed severe histological alterations. However, supplementation with EO improved SWM and partially restored the activities of antioxidant systems  and prevented neuronal cell damage.

P. graveolens EO has the potential in mitigating most of the adverse effects in the hippocampus and prevents SWM impairment induced by MET toxicity.

The present study investigated the role of the Basolateral Amygdala (BLA) N-methyl-D-aspartate  (NMDA) receptors in stress-induced spatial memory disturbance among the male Wistar rats.

The male Wistar rats (Average weight =200 g) were cannulated bilaterally in the BLA, and entered the study (n=6-8) after one week. They received seven electro–foot-shock stress sessions on seven consecutive days. Memantine (0.1, 1, and 5 µg/rat) or saline (0.5 µL/rat) was injected into the BLA, five minutes before each stress session. The control groups received the same doses of memantine and no stress. After the end of the stress sessions, blood samples were taken from all animals to evaluate their plasma corticosterone. Also, the spatial learning and memory of the study animals were evaluated using the Barnes maze method. The animals experienced five consecutive days of training on the maze for spatial learning. On the sixth day, their spatial memory was evaluated on the maze. Time, distance, the number of errors, and the taking strategy for reaching the target hole were considered as the parameters for the spatial learning and memory evaluation.

Stress increases the plasma corticosterone level, while memantine preadministration reduces the stress effects. Besides, stress increases the time and distance to the target hole and the number of errors. Stress changed the animals’ strategy from serial to random type. However, the intra-BLA memantine reversed all the disturbances induced by the stress.

This study indicated that the BLA glutamate NMDA receptors modulate the effect of stress on spatial learning and memory deficit.

The administration of 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy causes memory impairment, whereas neurogenesis improves memory and learning. Hence, this study evaluated the effects of MDMA on neurogenesis in the hippocampus of male rats.

Adult male Wistar rats received Intraperitoneal (IP) injections of MDMA (10 mg/kg). We assessed nestin, sex-determining region Y-box 2 (Sox2), and NeuroD expressions according to the immunohistochemistry analyses. 

MDMA reduced the expressions of nestin, Sox2, and NeuroD compared with the control groups. The reduction in NeuroD expression was age-related. 

MDMA possibly has negative effects on neurogenesis, which specifically results from impaired survival of newborn cells.

Sustained Attention (SA) failure is one of the main characteristics of Specific Learning Disorders (SLD). Recent studies have reported a positive effect of Cognitive Rehabilitation (CR) and Neurofeedback (NFB) on SA in SLD. Thus, the effectiveness of CR and NFB is well understood. This preliminary study aimed to compare the effects of CR and NFB on SA among the elementary school students with SLD, using a randomized controlled clinical trial.

In this preliminary randomized controlled clinical trial, 53 eligible students with SLD (based on DSM-5) within the age range of 7 to 10 years were randomly assigned in the NFB (n=18), CR (n=18), and control group (n=17). All the participants were evaluated for SA using the continuous performance test (CPT), at the time of entry to the study, and one month later. The intervention groups participated in 20 sessions of CR and 20 sessions of NFB, while the control group was evaluated without any intervention.

A total number of 24 boys and 36 girls in four groups (n=15) completed the study. The Mean±SD age of the participants in the CR, NFB, and control groups were 8.66±1.48 years, 8.40±1.73 years, and 8.53±1.63 years, respectively. Results showed a significant difference in the variables of the CPT between the study groups (P<0.05). Also, the CPT scores of the CR group were higher than that of the NFB group (P<0.001). 

This study supports that CR is more effective than NFB on SA in students with SLD.

For centuries, cannabinoids are known to be effective in pain relief. Itch is an unpleasant sensation that provokes a desire to scratch. Since itch and pain are two sensations sharing a lot in common, we aimed to investigate whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behavior and also observe whether modulation of nitric oxide (NO) production mediates the antipruritic effect of WIN 55,212-2.

Scratching behavior is induced by intradermal injection of serotonin (50 µg/50 µL/mouse) to BALB/c mice. The cannabinoid agonist WIN 55,212-2 (1, 3, 10 mg/kg, IP) was given 30 min before serotonin injection. To observe the effect of NO modulation on the antipruritic effect of cannabinoids, the endothelial nitric oxide synthase (NOS) inhibitor L-NAME (3 mg/kg, IP), the neuronal NOS inhibitor 7-nitroindazole (3 mg/kg, IP), and the NO precursor L-arginine (100 mg/kg, IP) were administered together with WIN 55,212-2. 

WIN 55,212-2 reduced serotonin-induced scratches at higher doses (3, 10 mg/kg; P<0.0001). The endothelial NOS inhibitor L-NAME, the neuronal NOS inhibitor 7-nitroindazole, and the nitric oxide precursor L-arginine did not influence the antipruritic action of WIN 55,212-2. When NO modulators were used alone, only the neuronal NOS inhibitor 7-nitroindazole attenuated serotonin-induced scratches (P<0.0001).

Our findings indicate that exogenous cannabinoids may attenuate serotonin-induced scratches and NO does not mediate the antipruritic effect of WIN 55,212-2. On the other hand, neuronal NOS inhibition may play a role in the production of serotonin-induced scratches.

The GABAergic system of the brain plays a key role in morphine tolerance and sensitization. As isoniazid is a modulator of the GABAergic system, the present study aims to understand whether isoniazid can influence the induction of tolerance and sensitization to the rewarding effects of morphine. 

The rewarding effects of morphine and isoniazid were assessed using a Conditioned Place Preference (CPP) procedure in female mice. Tolerance to the rewarding effects of morphine was induced with high-dose morphine (25 mg/kg, SC), twice a day, for four days. Also, the sensitization was induced with an effective dose of morphine (5 mg/kg, SC), once a day, for three days. During the induction of tolerance or sensitization, the different groups of mice received saline or isoniazid (25, 50, and 75 mg/kg, IP) one hour before each morphine injection.

Morphine (0.5-10 mg/kg, SC) produced a significant CPP, but isoniazid (25, 50, and 75 mg/kg, IP) did not induce place preference or place aversion in mice. Although an effective dose of morphine (5 mg/kg, SC) did not induce CPP in morphine tolerated mice, an ineffective dose (0.5 mg/kg, SC) could produce a significant CPP in morphine-sensitized animals. The administration of isoniazid before morphine (on the days of tolerance or sensitization induction) inhibited the development of tolerance or sensitization to the rewarding effect of morphine in the CPP paradigm.

Isoniazid can be a useful drug for the prevention of tolerance and sensitization to the rewarding effects of morphine.

Primary Diffuse Large B Cell Lymphoma of CNS (PCNSL) is a rare variant of Diffuse Large B Cell Lymphoma (DLBCL) and presents with an aggressive clinical course and usually resistant to commonly used therapy regimens. Recently, role of immune checkpoint molecules including PD-1 and PD-L1 confirmed in some solid tumors and lymphoma resulting tumor cells escape the immune system and help to survive and to spread. Inhibitors of PD-1 and PD-L1 have shown lasting responses in several solid and some hematological tumors, while limited studies evaluate checkpoint molecules on PCNSL.

In this study, we investigated PD-1 and PD-L1 expression by immunostaining on 71 patients with PCNSL and correlation with demographic data, location of the tumor, proliferation rate, cell of origin, and CD8 positive T cell infiltration in tumor microenvironment. 

16 from71 showed PD-1 expression, while PD-L1 expression were 42/71. No association was determined between PD-1/PD-L1 expression and gender, cell of origin, and proliferation rate, but a highly significant difference was determined between the infiltration of CD8 positive T cells in two groups of PD-1/PD-L1 positive and negative. 

This study revealed expression of check point molecules in remarkable number of PCNSL which may open new therapeutic recommendations in this aggressive lymphoma type.

Hypoxia via expression of Hypoxia Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) increased in hypoxia condition. BACE1 trigger a cascade of pathological events resulting in AD. Crocin act as memory improvement agent but its molecular mechanism is not well-known. So, in this study, the effect of crocin on spatial memory, HIF-1α and BACE1 gene expression were investigated in rat offspring under maternal hypoxia.

Female pregnant rats on the 20th day of pregnancy were divided into 4 groups including: sham, crocin treated, hypoxia and hypoxia group treated with crocin. In hypoxia groups, pregnant rats were exposed to the 7% oxygen and 93% nitrogen intensity for 3 hours. In the crocin treated group, crocin (30 mg/kg) injected at P14-28, (i.p). At the end, Morris water maze was used to assess spatial memory and Real-Time PCR analysis was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.

Maternal hypoxia impaired memory task compared to the sham group. But crocin treatment improved cognitive behavior. HIF-1α and BACE1 expression were unregulated in the brain of offspring in hypoxia group. Crocin treatment could attenuate the expression of both genes.

According to our results, down- regulation of HIF-1α and BACE1 gene expression in the brain of rat offspring after crocin treatment can be suggested as molecular mechanism for crocin to improve spatial memory.

of the study: Post-training administration of glucocorticoids enhance memory consolidation of inhibitory avoidance learning. Given the involvement of 5-HT6 receptors in memory processing and the interaction of glucocorticoids with the brain serotonergic system in modulating memory processing, we investigated whether the effect of glucocorticoids on the consolidation of emotionally arousing training depends on hippocampal 5-HT6 receptors. 

Rats were trained in an inhibitory avoidance task and immediately received the systemic injections of corticosterone (CORT) as well as the intra-hippocampal injections of 5-HT receptors agonist or antagonist. The memory retention test was done 48 hours after training and immediately after the behavioral test, the animals were sacrificed and the hippocampi (left and right) rapidly dissected out for molecular studies.

Post-training injections of different doses of CORT (1.25, 2.5, 5, and 10 mg/kg) enhanced memory retention in a dose-dependent manner. The CORT-induced enhancement of memory consolidation was blocked by bilateral intra-hippocampal injections of 5-HT6 receptor antagonist SB271046 (5 or 10 ng/per side), but not agonist EMD386088 (5 or 10 ng/per side). Furthermore, systemic CORT reduced 5-HT6 receptor mRNA and protein expression in the hippocampus. Both doses of 5-HT6 receptor agonist and antagonist significantly enhanced and reduced the expression of the 5-HT6 receptor, respectively, and both ligands at the higher dose (10 ng) enhanced memory consolidation. Moreover, CORT injection attenuated and enhanced, respectively, the effects of agonist and antagonist on 5-HT6 receptor expression. 

These behavioral and molecular findings indicated an interaction between glucocorticoids and hippocampal 5-HT6 receptors in the consolidation of emotionally arousing experiences.

Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD. 

The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway. 

No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters. 

Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.

Diabetes mellitus has harmful effects on body functions, such as learning and memory. According to the role of exercise and medicinal plants on body health, the purpose of this study was to survey the effect of combined aerobic training and the use of Ripe Pistachio Hulls (RPH) hydro-alcoholic extract on learning and memory in streptozotocin-induced diabetic male rats.

In this experimental study, 42 male Wistar rats weighing 250-280 g were used in 6 groups with an equal number of 7 rats in each one. Streptozotocin (STZ) (50 mg / kg)was used to induce diabetes , and the test protocol was applied for 8 weeks. Passive avoidance memory was assessed using a step-through passive avoidance apparatus (shuttle box). SPSS software was used to analyze the data and P<0.05 was significant.

The results showed that step-through latency in the acquisition trial (STLa) was not significantly different among groups. Step-through latency in retrieval (STLr 24) test significantly reduced and time spent in The Dark Compartment (TDC) decreased in treated groups compared with the diabetic control groups (P<0.001). Also, there was no significant difference between the STZ and saline diabetic groups.

The findings of this study revealed that the RPH hydro-alcoholic extract and aerobic exercise could improve passive avoidance memory in streptozotocin diabetic rats. Meanwhile, they might be an adjuvant therapy combined with other traditional medicine.

This study aimed to evaluate the reliability and validity of an Iranian computerized memory battery modeled after the Betula study.

This study aimed to evaluate the reliability and validity of an Iranian computerized memory battery modeled after the Betula study (Nilsson et al., 1997). The researchers developed this battery as an assessment tool in the Sepidar prospective cohort study. One hundred and ninety-nine participants aged 19-83 years were tested extensively on different aspects of memory. Exploratory factor analysis of the data demonstrated factors similar to those reported by the Betula study. 

The authors succeeded to converge the cross-sectional findings of the study and the data from longitudinal studies of memory aging by correcting possible cohort effects. Investigating age differences in episodic and semantic memory factor scores corrected by education and socioeconomic status revealed no significant difference between younger and older adults before ages 53 to 60, though linear age-related declines existed thereafter.

The results support the reliability and construct validity of this computerized battery for memory assessment in Iranian adults.

Whole Exome Sequencing (WES) has been increasingly utilized in genetic determinants of various inherited diseases.

We applied WES for a patient presenting 3-Methylglutaconic Aciduria (MEG), Deafness (D), Encephalopathy (E), and Leigh-like (L) syndrome. Then Sanger sequencing was used for the detected variant validation. 

We found an insertion, rs797045105 (chr6, 158571484, C>CCATG), in the SERAC1 gene with homozygous genotype in the patient and heterozygous genotype in her unaffected parents. Notably, bioinformatics analysis using mutation taster (prob>0.99) and DDIGin (prob=86.51) predicted this mutation as disease-causing. Also, the variant was not present in our database, including 700 exome files.

These findings emphasize the pathogenicity of rs797045105 for MEGDEL syndrome. On the other hand, our data shed light on the significance of WES application as a genetic test to identify and characterize the comprehensive spectrum of genetic variation and classification for patients with neuro- metabolic disorders.

State-dependent (STD) memory is a process, in which the learned information can be optimally retrieved only when the subject is in the state similar to the encoding phase. This phenomenon has been widely studied with morphine. Several studies have reported that Pentylenetetrazole (PTZ) impairs memory in experimental animal models. Due to certain mechanistic interactions between morphine and PTZ, it is hypothesized that PTZ may interfere with the morphine-STD. The cyclic adenosine monophosphate Response Element-Binding (CREB) is considered as the main downstream marker for long-term memory. This study was designed to determine the possible interaction between PTZ and morphine STD and the presumable changes in CREB mRNA.

In an Inhibitory Avoidance (IA) model, posttraining morphine (2.5, 5, and 7.5 mg/kg-i.p.) was used. The pre-test morphine was evaluated for morphine-induced STD memory. Moreover, the effect of a pre-test PTZ (60 mg/kg-i.p.) was studied along with morphine STD. Locomotion testing was carried out using open-field. Eventually, using real-time-PCR, the CREB mRNA changes in the hippocampus were evaluated.

Posttraining MOR (7.5 mg/kg-i.p.) impaired IA memory (P<0.001). The pre-test injection of similar doses of morphine recovered the morphine-induced memory impairment (P<0.001). The pre-test PTZ impaired the IA memory recall (P<0.001); however, the pre-test PTZ along with morphine STD potentiated the morphine-induced STD (P<0.001). Alterations in CREB mRNA were observed in all groups. No difference was seen in the locomotor activity.

Presumably, the certain interactive effect of PTZ on morphine-induced STD is mediated through gamma-aminobutyric acid and opioid systems via CREB signaling.