Altered D2 receptor and transcription factor EB expression in offspring of aggressive male rats, along with having depressive and anxiety-like behaviors.

MATERIALS AND METHODS: In this study we have evaluated the behavioral mood variations, and expression of DR-D2 and TFEB genes in the amygdala and PFC of aggressive male rats' offspring. RESULTS: Anxiety and depression-like behaviors were observed, but intra-ventricle injection of DR-D2 antagonist (Sulpiride) has shown to be efficient in reducing negative behavioral changes in offspring. Furthermore, DR-D2 gene expression was increased in the amygdala and PFC of aggressive male rats' offspring, which the injection of Sulpiride decreased it significantly. TFEB gene expression was also decreased in the amygdala and PFC of aggressive male rats' offspring, but the blockade of DR-D2 had no effect on it. CONCLUSIONS: The current data suggests the possible influence of dopaminergic receptors D2 and TFEB genes on the behavioral changes which is modified by having an aggressive father.

Response to Fluvoxamine in the Obsessive-Compulsive Disorder Patients: Bayesian Ordinal Quantile Regression.

BACKGROUND: Obsessive-Compulsive Disorder (OCD) is a chronic neuropsychiatric disorder associated with unpleasant thoughts or mental images, making the patient repeat physical or mental behaviors to relieve discomfort. 40-60% of patients do not respond to Serotonin Reuptake Inhibitors, including fluvoxamine therapy. INTRODUCTION: The aim of the study is to identify the predictors of fluvoxamine therapy in OCD patients by Bayesian Ordinal Quantile Regression Model. METHODS: This study was performed on 109 patients with OCD. Three methods, including Bayesian ordinal quantile, probit, and logistic regression models, were applied to identify predictors of response to fluvoxamine. The accuracy and weighted kappa were used to evaluate these models. RESULTS: Our result showed that rs3780413 (mean=-0.69, sd=0.39) and cleaning dimension (mean=-0.61, sd=0.20) had reverse effects on response to fluvoxamine therapy in Bayesian ordinal probit and logistic regression models. In the 75th quantile regression model, marital status (mean=1.62, sd=0.47) and family history (mean=1.33, sd=0.61) had a direct effect, and cleaning (mean=-1.10, sd=0.37) and somatic (mean=-0.58, sd=0.27) dimensions had reverse effects on response to fluvoxamine therapy. CONCLUSION: Response to fluvoxamine is a multifactorial problem and can be different in the levels of socio-demographic, genetic, and clinical predictors. Marital status, familial history, cleaning, and somatic dimensions are associated with response to fluvoxamine therapy.

Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder.

WHAT IS KNOWN AND OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first line of medication for OCD treatment; however, 40%-60% of patients with OCD do not respond to SSRIs adequately. There are growing pieces of evidence which suggest a significant role for the glutamatergic system in the genesis of OCD and its consequent treatment. In the present study, we aimed to assess the association of SLC1A1 polymorphisms (rs301430, rs2228622 and rs3780413) with OCD and its clinical characteristics, as well as the importance of these SNPs in the response of OCD patients to SSRI pharmacotherapy. METHODS: Sample study consisted of 243 OCD cases and 221 control subjects. Patients were treated 12 weeks with fluvoxamine (daily dose: 150-300 mg). Based on the reduction in obsessive and compulsive severity scores using Y-BOCS severity scale, patients were classified as responders, non-responders and refractory. A total of 239, 228 and 215 patients were genotyped for rs301430, rs2228622 and rs3780413, respectively, by the means of PCR-RFLP. RESULTS AND DISCUSSION: No association was detected between SLC1A1 SNPs and OCD, except an association between the familial form of the disease in males with rs2228622 (P = 0.033). The results of pharmacogenetic studies revealed the associations of two SLC1A1 SNPs, rs2228622 (P = 0.031) and rs3780413 (P = 0.008), with treatment response. WHAT IS NEW AND CONCLUSION: Results of the current study suggest a role for the glutamate transporter in OCD treatment response with SSRIs which should encourage researchers to further investigate the importance of glutamate transporter in OCD pharmacogenetics.

Association of HTR1A gene polymorphisms with obsessive-compulsive disorder and its treatment response: the influence of sex and clinical characteristics.

OBJECTIVE: There have been controversial results in the literature on the association between HTR1A polymorphisms (rs10042486, C-1019G, and Gly272Asp) and obsessive-compulsive disorder (OCD). Here, the plausibility for such genetic and pharmacogenetic association was investigated by assessing a sample of Iranian OCD patients. METHOD: OCD patients had fulfilled the criteria for DSM-IV-TR with Y-BOCS scores higher than 9. A total of 207 controls and 205 patients' blood samples were genotyped by means of PCR-RFLP. RESULTS: The results showed that there was no association between these three SNPs and the treatment response. The distribution of rs10042486 genotypes was significantly different in the patients compared to the controls. The association analyses of the C-1019G showed significant differences in the genotypic frequency of the patients with or without a positive family history of psychiatric disorders. Similar differences in female patients were also observed. We found that the age of onset also associates with the C-1019G polymorphism but only in the female patients. No association of Gly272Asp polymorphism and OCD was observed in this study. CONCLUSION: We concluded that among the HTR1A polymorphisms, only the association of rs10042486 CT genotype and OCD was statistically significant. The association of C-1019G with OCD by considering the age of onset and family history was just significant in the female patients. No significant association between the studied HTR1A SNPs with treatment response was observed. Acquiring both positive and negative pharmacogenetic outcomes in each population helps to select the appropriate medication for a particular patient with fewer side effects.

A novel nonsense mutation in WNK1/HSN2 associated with sensory neuropathy and limb destruction in four siblings of a large Iranian pedigree.

BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is an autosomal recessive disorder with predominant sensory dysfunction and severe complications such as limb destruction. There are different subtypes of HSAN2, including HSAN2A, which is caused by mutations in WNK1/HSN2 gene. METHODS: An Iranian family with four siblings and autosomal recessive inheritance pattern whom initially diagnosed with HSAN2 underwent whole exome sequencing (WES) followed by segregation analysis. RESULTS: According to the filtering criteria of the WES data, a novel candidate variation, c.3718C > A in WNK1/HSN2 gene that causes p.Tyr1025* was identified. This variation results in a truncated protein with 1025 amino acids instead of the wild-type product with 2645 amino acids. Sanger sequencing revealed that the mutation segregates with disease status in the pedigree. CONCLUSIONS: The identified novel nonsense mutation in WNK1/HSN2 in an Iranian HSAN2 pedigree presents allelic heterogeneity of this gene in different populations. The result of current study expands the spectrum of mutations of the HSN2 gene as the genetic background of HSAN2A as well as further supports the hypothesis that HSN2 is a causative gene for HSAN2A. However, it seems that more research is required to determine the exact effects of this product in the nervous system.

Association of the functional serotonin transporter haplotype with familial form of obsessive compulsive disorder in Iranian patients.

OBJECTIVE: Several polymorphisms have been reported in the 5-HTTLPR of the serotonin transporter gene (SLC6A4). Family-based evidences for the association of 5-HTTLPR polymorphisms with OCD were previously reported but results were controversial. The present study investigated the possible correlation of SLC6A4 polymorphisms (5-HTTLPR, rs25532, rs25531) in Iranian OCD patients considering gender, age of onset, family history of psychiatric disorders, obsessive and compulsive subtypes and severities. METHODS: The included OCD patients fulfilled the criteria for DSM-IV-TR whom Y-BOCS score was more than 9. Blood samples (184 cases and 192 controls) were genotyped by means of PCR-RFLP. RESULTS: Mean of Y-BOCS scores of included patients was 20.1 ± 0.69. Rs25532 CC genotype showed significant association with OCD in men and were detected more in the patients reported positive family history of psychiatric disorders but the other single loci (5-HTTLPR and rs25531) did not associate with OCD. Haplotype analysis showed significant association of 14-A variant with OCD and revealed the association of 14-A/14-A genotype with familial form of OCD. CONCLUSIONS: The findings of this study showed the association of SLC6A4 variants with familial form of OCD and proposed stratified analyses in the genetic studies facilitate identification of genetic risk factors for this heterogeneous disorder.

Paternal Aggression in Early-life Impairs the Spatial Memory and Passive Avoidance Learning in Adulthood of Male Rats: The Possible Role of DRD2.

Introduction: Negative early-life experiences (e.g. having an aggressive father) can leave long-lastingimpacts on the behavior. However, it is not clear if they influence learning and memory. Methods: In this study, we investigated the influences that the presence of an aggressive father had on the level of passive avoidance learning and spatial memory. We also studied the changes in the dopamine receptor D2 (DRD2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) gene expression in the hippocampus. Then, we evaluated if a DRD2 antagonist (sulpiride, 0.125, 0.25, or 0.5 µg/rat) could modulate these changes. Results: We found that the subjects exposed to early-life stress made by aggressive fathers had impaired passive avoidance learning and spatial memory compared to subjects with normal fathers. Treatment with sulpiride improved passive avoidance learning and spatial memory in rats with aggressive fathers. The rats with aggressive fathers also had higher expression of the DRD2 gene in their hippocampus than those with normal fathers, while the PGC-1α gene expression was not different among groups. Treatment with sulpiride (0.125, 0.25, or 0.5 µg/rat) reduced the DRD2 gene expression in those with aggressive fathers to the normal level compared to those with normal fathers. Conclusion: These data suggest that having and living in a shared place with an aggressive father, even without any physical contact, can detrimentally affect passive avoidance learning and spatial memory which is accompanied by the increased expression of the DRD2 gene. Also, sulpiride as a dopaminergic antagonist could reverse this process. Highlights: Having and living with an aggressive father reduced learning and memory in offspring.Having and living with an aggressive father during early life increased DRD2 gene expression.Sulpiride improved learning and memory and also normalized DRD2 gene expression.A combination of genetic and environmental factors may modulate learning and memory. Plain Language Summary: In this study, we looked at how having an aggressive father, can affect behavior in the long term. We wanted to find out if this factor influences learning and memory. To do this, we investigated how the presence of an aggressive father affected passive avoidance learning and spatial memory in subjects. We also examined specific genes in the brain, called DRD2 and PGC-1α, which are known to be involved in learning and memory. Specifically, we wanted to see if the expression of these genes in the hippocampus (a region of the brain important for memory) was affected by having and presence of an aggressive father. To understand the role of the DRD2 gene further, we used a drug called sulpiride, which blocks the action of DRD2. We administered sulpiride to the subjects with aggressive fathers to see if it could reverse any negative effects on learning and memory. What we found was that subjects that had aggressive fathers had impaired passive avoidance learning and spatial memory compared to those with normal fathers. However, when we treated the subjects with sulpiride, their learning and memory improved. Additionally, we observed that rats with aggressive fathers had higher levels of the DRD2 gene in their hippocampus, while the PGC-1α gene expression was not different among the groups. The administration of sulpiride reduced the expression of the DRD2 gene in rats with aggressive fathers, bringing it back to normal levels similar to those with normal fathers. These findings suggest that having and living in the same environment as an aggressive father, even without direct physical contact, can negatively impact passive avoidance learning and spatial memory. This effect seems to be associated with increased expression of the DRD2 gene. However, using sulpiride as a dopaminergic antagonist can reverse this process and improve learning and memory in these subjects.

Paternal stress in rats increased oxytocin, oxytocin receptor, and arginine vasopressin gene expression in the male offspring amygdala with no effect on their social interaction behaviors.

OBJECTIVE: Environmental and hereditary factors play roles in shaping the personality of offspring which are often associated with gene expression alterations. The long-term effects of the environment that are modulated by the epigenetic mechanisms can be even transmitted to the next generations. This study aimed to investigate the effects of paternal stress, such as paternal aggression and food deprivation, on the social interaction behaviors of offspring in adulthood and the expression of genes that are associated with these behaviors. METHODS: The intruder-resident method, followed by an electric shock, was used to induce aggression in male Wistar rats before mating. To induce food deprivation, father rats were given 10 g pellets every day without restriction on water consumption for 2 weeks before mating. Social interactions of the male offspring were evaluated at the age of 8 weeks using a three-chamber social interaction test. Real-time PCR was applied to quantify the expression levels of oxytocin (OXT), oxytocin receptor (OXTR), and arginine vasopressin (AVP) genes in the amygdala of offspring. One-way analysis of variance was used to compare the means of experimental groups. RESULTS: The results did not show significant changes in the social interaction behaviors for the offspring of aggressive and food-deprived fathers compared to the control group. However, molecular investigations indicated increased levels of OXT, OXTR, and AVP gene expression in the offspring amygdala of aggressive and food-deprived fathers. CONCLUSION: The results showed that paternal stress, such as aggression and food deprivation, induced gene expression alterations in the offspring, although they did not affect their social interaction behaviors.

The Synergistic Anti-Apoptosis Effects of Amniotic Epithelial Stem Cell Conditioned Medium and Ponesimod on the Oligodendrocyte Cells.

Multiple sclerosis is a chronic inflammatory and neurodegenerative disease of the central nervous system. The current treatment of Multiple sclerosis is based on anti-inflammatory disease-modifying treatments, which can not regenerate myelin and eventually neurons. So, we need new approaches for axonal protection and remyelination. Amniotic epithelial stem cells amniotic epithelial cells, as a neuroprotective and neurogenic agent, are a proper source in tissue engineering and regenerative medicine. Due to differentiation capability and secretion of growth factors, AECs can be a candidate for the treatment of MS. Moreover, sphingosine-1-phosphate (S1P) receptor modulators were recently approved by FDA for MS. Ponesimod is an S1P receptor-1 modulator that acts selectively as an anti-inflammatory agent and provides a suitable microenvironment for the function of the other neuroprotective agents. In this study, due to the characteristics of AECs, they are considered a treatment option in MS. The conditioned medium of AECs concurrently with ponesimod was used to evaluate the viability of the oligodendrocyte cell line after induction of cell death by cuprizone. Cell viability after treatment by conditioned medium and ponesimod was increased compared to untreated groups. Also, the results showed that combination therapy with CM and ponesimod had a synergistic anti-apoptotic effect on oligodendrocyte cells. The combination treatment with CM and ponesimod reduced the expression of caspase-3, caspase-8, Bax, and Annexin V proteins and increased the relative BCL-2/Bax ratio, indicating inhibition of apoptosis as a possible mechanism of action. Based on these promising results, combination therapy with amniotic stem cells and ponesimode could be a proper alternative for multiple sclerosis treatment.

OPRM1 and CYP3A4 association with methadone dose in Iranian patients undergoing methadone maintenance therapy.

BACKGROUND: Investigations proposed that genetic polymorphisms within proteins in methadone pharmacokinetic and pharmacodynamics are critical factors in determination of methadone dose in methadone maintenance therapy (MMT). OBJECTIVE: This study aimed to assess the associations between two polymorphisms, CYP3A4 (rs2740574) and OPRM1 (rs1799971), with dose of methadone in Iranian patients undergoing MMT. METHODS: A total of 124 Iranian male subjects aged 18-65 years old who were confirmed to be addicted by the addiction diagnostic tests and underwent MMT were assessed. Patients were divided into three groups of low (less than 40 mg/day), moderate (more than 40 mg/day and less than 110 mg/day) and high (more than 110 mg/day) methadone dose consumption. DNAs of included patients were extracted from their blood samples and were assessed for CYP3A4 and OPRM1 polymorphisms. RESULTS: Results showed that there was no significant association between the studied polymorphisms and methadone dose in Iranian addicted patients underwent MMT (P > 0.05). CONCLUSIONS: CYP3A4 and OPRM1 single variations cannot explain variability in methadone dosage in MMT. Studying the interactions of more genetic factors in larger samples may elucidate factors influencing the required dose of methadone and better individualized therapy.

Quality of early-life maternal care predicts empathy-like behavior in adult male rats: Linking empathy to BDNF gene expression in associated brain regions.

Empathy is the ability to experience a shared affective state as others. It enhances group living and manifests itself as helping behavior towards a distressed person. It also can flourish by nurturing. Recent findings suggest that rodents exhibit empathy-like behavior towards their conspecifics. However, the role of early-life experiences (e.g., maternal care) is not clear on the development of empathy-like behavior. Moreover, brain-derived neutrophilic factor (BDNF) is a pivotal protein in modulating the brain's function and behaviors. Evidence suggests that the expression of the BDNF gene can be affected by the quality of maternal care. In this study, we questioned whether variation in maternal care modulates empathy-like behavior of male rats in adulthood. Additionally, gene expression of BDNF was measured in the amygdala, hippocampus, insula, anterior cingulate cortex, prefrontal cortex, and striatum in these adult male rats. Based on the pattern of maternal care, the offspring were divided into high maternal care (HMC) and low maternal care (LMC) groups. We confirmed that the early-life experience of HMC significantly promoted the empathy-like behavior of rats in adulthood compared to LMC. In terms of gene expression, the HMC group consistently had higher BDNF gene expression in all studied regions, except anterior cingulate cortex which groups were not different. Taken together, it suggests that maternal care in infancy predicts empathy-like behavior in adulthood and differences in BDNF gene expression in different brain regions may reflect the underlying mechanism.

Preconditioning by ultra-low dose of tramadol reduces the severity of tramadol-induced seizure: Contribution of glutamate receptors.

Tramadol, a weak agonist of mu-opioid receptors, causes seizure via several mechanisms. Preconditioning has been purposed to reduce the epileptic seizures in animal models of epilepsy. The preconditioning effect of tramadol on seizure is not studied yet. This study was designed to evaluate the preconditioning effect of ultra-low dose of tramadol on the seizures induced by tramadol at high dose. Furthermore, regarding the critical role of glutamate signaling in the pathogenesis of epilepsy, the effect of preconditioning on some glutamate signaling elements was also examined. Male Wistar rats received tramadol (2 mg/kg, i.p) or normal saline (1 mL/kg, i.p) in preconditioning and control groups, respectively. After 4 days, the challenging tramadol dose (150 mg/kg) was injected to all rats. Epileptic behaviors were recorded during 50 min. The expression of Norbin (as a regulator of metabotropic glutamate receptor 5), Calponin3 (as a regulator of excitatory synaptic markers), NR1 (NMDA receptor subunit 1) and GluR1 (AMPA receptor subunit 1) was measured in hippocampus, prefrontal cortex (PFC) and amygdala. Preconditioning decreased the number and duration of tremors and tonic-clonic seizures. Norbin, Calponin3, NR1 and GluR1 expression were decreased in hippocampus, and preconditioning had no effect on them. In contrast, it increased Norbin expression in PFC and amygdala, and attenuated NR1 and GluR1 upregulation following tramadol at high dose. These findings indicated that preconditioning by ultra-low dose of tramadol protected the animals against seizures following high dose of tramadol mediated, at least in part, by Norbin up regulation, and NR1 and GluR1 down regulation.

Quality assessment of DNA and hemoglobin by Fourier transform infrared spectroscopy in occupational exposure to extremely low-frequency magnetic field.

Previous studies have shown the effect of extremely low-frequency (ELF) magnetic fields on the hematopoietic system. However, molecular modification and biological toxicity are not known yet. The aim of this study was to investigate the effect of occupational exposure to ELF magnetic field on the hemoglobin and DNA alteration using Fourier transform infrared (FTIR) spectroscopy. Twenty nine individuals were selected among those working as the controller in a powerhouse in order to be studied as the population exposed to ELF magnetic field. Control group comprised of 29 administrative employees voluntarily participated who were matched with the exposed subjects in terms of sex, age, work experiences, smoking habit, and socioeconomic status. DNA and hemoglobin were extracted from blood samples and then were studied by FTIR spectroscopy. The results showed the level of magnetic field exposure was between 0.38 to 50 µT in the exposed subjects while the level of magnetic field exposure was between 0.19 and 20 µT for the unexposed people. Hemoglobin level was equal to 15.67 ± 1.42 g/dL for exposed subjects which is significantly lower than that of the unexposed people (p = 0.0001). There was a significant alteration in CH content and COO structure of the hemoglobin structure. Moreover, DNA showed significant changes by functional group of organic base. This change in the structure of DNA and hemoglobin can lead to the creation of risks in human health. In conclusion, FTIR method could reveal the quality of DNA and hemoglobin structure in subjects after exposure to ELF magnetic field.

BDNF association study with obsessive-compulsive disorder, its clinical characteristics, and response to fluvoxamine-treatment in Iranian patients.

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder with complex genetic inheritance. Findings suggest a role for brain-derived neurotrophic factor (BDNF) in OCD, but reports are limited. Here we studied the association of BDNF polymorphisms rs6265 and rs2883187 with OCD and its clinical characteristics in Iranian patients as well as the fluvoxamine-treatment outcome of OCD patients. Iranian OCD patients who were diagnosed according to DSM-IV-TR entered the study. DNAs were extracted from blood samples and were genotyped by means of PCR-RFLP. A total of 200 OCD cases and 225 controls for rs6265 and 219 cases and 224 controls for rs2883187 were studied in the genetic association analysis. Pharmacotherapy was defined as 12 weeks treatment with fluvoxamine (daily dose: 150-300 mg), and patients were classified into 3 groups (responders, nonresponders, and refractory) based on the reduction in their Y-BOCS severity scores. Data of 94 patients for rs6265 and 106 patients for rs2883187 was analyzed to evaluate the association of these single nucleotide polymorphism (SNPs) with treatment response. A significant association was detected between the BDNF polymorphism rs2883187 and OCD (p = .00). The other BDNF polymorphism, rs6265, was not associated with OCD, but a weak association with the cleaning-contamination subtype was detected (p = .038). No association was detected between BDNF SNPs and sex, age of onset, and family history. None of the studied BDNF SNPs or their haplotypes were associated with fluvoxamine treatment response. Results propose BDNF SNP, rs2883187, as a candidate genetic factor in OCD but not in OCD treatment response with fluvoxamine. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Oxytocin protects against 3-NP induced learning and memory impairment in rats: Sex differences in behavioral and molecular responses to the context of prenatal stress.

Learning and memory impairment manifests years before the onset of motor impairments in Huntington's disease (HD). Oxytocin (OXT), as a neurohypophyseal neuropeptide has a key role in both learning and memory. Hence, we investigated possible protective effect of OXT on instrumental fear conditioning memory impairment by 3-Nitropropionic acid (3-NP) induced HD, considering sex and prenatal stress effects. Pregnant Wistar rats were exposed to restraint stress for 45 min three times a day, from the gestational day 8 to parturition. 3-NP was injected intraperitoneally (20 mg/kg) for 5-7 days after OXT (10 µg/µl. icv) injection in the male and female offspring rats respectively. One day after the last 3-NP injection, the rotarod and passive avoidance task were conducted. As the key molecular determinants in metabolism and memory processes, we measured the activity of acetylcholinesterase (AChE) and the amount of receptor interacting protein3 (RIP3) in the hippocampus, prefrontal cortex, striatum and amygdala using spectrophotometry and western blotting respectively. Besides, the activity of glutamate dehydrogenase was measured (GDH) as a chain between metabolism and memory formation. The results indicated that OXT improved learning and memory impairment caused by 3-NP or prenatal stress in both sexes. It was along with a significant decrease in the level of RIP3, AChE and GDH activities. However, in the presence of prenatal stress, the OXT could improve 3-NP induced learning and memory impairments just in female rats. So it could be suggested as an effective neurotherapeutic agent in diseases such as HD, but its sex and context dependency should be considered carefully.

Inflammation but not programmed cell death is activated in methamphetamine-dependent patients: Relevance to the brain function.

Animal studies have shown that methamphetamine (MA) induces neurodegeneration through programmed cell death, however, the effects of MA on human brain and the extent of induced neural degeneration is not well understood. Given that the dose and duration of MA administration differ in animals and humans, we evaluated MA effects on active users considering brain damage mechanisms. Nineteen active MA-dependent patients and 18 healthy controls performed the color-word Stroop task, during fMRI and their blood samples were collected. Human enzyme-linked immunosorbent assays (ELISA) and quantitative PCR were applied to measure circulating proteins and miRNAs involved in various programmed cell death pathways (apoptosis, necroptosis, and autophagy), brain damage and neuroinflammation. Results showed the performance deficit in color-word Stroop task in MA abusers as well as higher activations of the right inferior and middle temporal gyri detected by fMRI. Structural MRI revealed increased white matter volume in MA-dependent patients in the superior and medial frontal gyri, and left/right middle temporal gyrus. Molecular analyses detected no significant differences in the plasma levels of the studied proteins and miRNAs of MA-dependent patients and controls except the higher levels of MBP, S100B, and TNFα in MA abusers. Results showed that MA induced physiological and structural changes accompanied by inflammation and release of damage-associated molecules in MA-dependent patients.

Frontocingulate Dysfunction Is Associated with Depression and Decreased Serum PON1 in Methamphetamine-Dependent Patients.

INTRODUCTION: Studies have been reported that frequent use of methamphetamine (MA) is associated with brain function impairment, mood disorders and excessive free radical production accompanied by the decreased level of the antioxidant response elements, but no study investigated their correlations simultaneously. In the current study, the correlation of brain function, depression and anxiety levels, and the serum levels of PON1 (an antioxidant) in MA-dependent patients were investigated. METHODS: Nineteen active MA abusers and 18 control subjects performed color-word Stroop task during fMRI and the state of their depression, anxiety, and stress were measured by the Depression, Anxiety and Stress Scale-21 Items (DASS-21) questionnaire. Their blood samples were collected to measure the level of PON1 by the human enzyme-linked immunosorbent assay (ELISA) kit and its correlation with the measured variables was studied. RESULTS: Analysis of fMRI findings showed frontocingulate dysfunction in Stroop effect condition, including left anterior cingulate cortex, paracingulate gyrus, superior frontal gyrus, and frontal pole in MA-dependent patients, which was associated with a higher level of depression and decreased level of serum PON1 in these patients. DISCUSSION: The results of the current study showed that MA-dependency is associated with frontocingulate dysfunction, decreased serum PON1 concentration, and increased depression/anxiety, which is worth to be more studied to elucidate their roles in the pathophysiology of MA addiction.

Peroxisomal Malfunction Caused by Mitochondrial Toxin 3-NP: Protective Role of Oxytocin.

Peroxisomes are single membrane cell organelles with a diversity of metabolic functions. Here we studied the peroxisomal dysfunction and oxidative stress after 3-nitropropionic acid (3-NP) induced neurotoxicity and the possible protective effects of oxytocin. Adult male and female rats were subjected to OXT and/or 3-NP treatment. The antioxidant enzymes, Superoxide dismutase (SOD) and Catalase (CAT) activities as well as expression level of Peroxin 14 (Pex14), a marker for peroxisomal number and Peroxisomal membrane protein of 70 kDa (PMP70), a metabolic transporter in peroxisome in different brain regions of both sexes were studied. The results indicated that 3-NP significantly decreased the expression level of Pex14 and PMP70 in various studied areas in male and female rats. In addition, 3-NP reduced the SOD and CAT activity in different brain regions in both sexes. OXT treatment increased the expression level of peroxisomal proteins Pex14 and PMP70 which are representative of peroxisome performance improvement. Besides, it ameliorated the antioxidant system capability through increasing the activity of the SOD and CAT in all studied brain regions including Striatum, Hippocampus, Prefrontal Cortex and Amygdala with no differences in male and female rats. This study demonstrated that toxin 3-NP, could ultimately cause peroxisomal malfunction and so determines the contribution of peroxisomal dysfunction in the etiology of HD pathology. OXT significantly increased peroxisomal function and antioxidant system defense capability, therefore illustrates that OXT might be an alternate treatment approach for the neurodegenerative diseases like HD.

Fluvoxamine treatment response prediction in obsessive-compulsive disorder: association rule mining approach.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive thoughts or repetitive behaviors. Clinicians use serotonin reuptake inhibitors (SRIs) for OCD treatment, but 40%-60% of the patients do not respond to them adequately. Here, we described an association rule mining approach for treatment response prediction using an Iranian OCD data set. PATIENTS AND METHODS: Three hundred and thirty OCD patients fulfilling DSM-5 criteria were initially included, but 151 subjects completed their pharmacotherapy which was defined as 12-week treatment with fluvoxamine (150-300 mg). Treatment response was considered as >35% reduction in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score. Apriori algorithm was applied to the OCD data set for extraction of the association rules predicting response to fluvoxamine pharmacotherapy in OCD patients. We considered the association of each attribute with treatment response using interestingness measures and found important attributes that associated with treatment response. RESULTS: Results showed that low obsession and compulsion severities, family history of mental illness, illness duration less than 5 years, being married, and female were the most associated variables with responsiveness to fluvoxamine pharmacotherapy. Meanwhile, if an OCD patient reported a family history of mental illness and his/her illness duration was less than 5 years, he/she responded to 12-week fluvoxamine pharmacotherapy with the probability of 91%. We also found useful and applicable rules for resistant and refractory patients. CONCLUSION: This is the first study where association rule mining approach was used to extract predicting rules for treatment response in OCD. Application of this method in personalized medicine may help clinicians in taking the right therapeutic decision.