Role of modafinil in the treatment of patients with methamphetamine dependence; An update on randomized, controlled clinical trial

Purpose: Methamphetamine is a powerful, highly addictive stimulant which affects the central nervous system. Here we evaluated the efficacy of modafinil for the treatment of patients with MA dependence.Methods: A randomized parallel controlled trial study was designed to compare the effectiveness of take-home, self-administered modafinil treatment in the intervention and the controlled group in three months. The primary outcome measurements were severity and duration of craving, and self-reported methamphetamine consumption, which was confirmed by urine drug test.Results: The relapse rate in the intervention group was 40%, and the controlled group was 75%, indicating a decrease in relapse rate of MA in the intervention group. During the three months, the severity and the duration of the drug abuse craving in the intervention group were less than thecontrolled group. Patients in the intervention group experienced an increase in the retention rate and a decrease in the slip rate.Conclusion: The use of modafinil is not only effective on craving and relapse reduction, but also changes urine drug screens of patients with MA dependence to negative. The modafinil is safely indicated as an absolutely effective medication to reduce withdrawal symptoms and the craving ofpatients with MA dependence. Keywords: Modafinil, Methamphetamine dependence, Effectiveness, Clinical tria

Role of modafinil in the treatment of patients with methamphetamine dependence: An update on randomized, controlled clinical trial

Purpose: Methamphetamine is a powerful, highly addictive stimulant which affects the central nervous system. Therefore, this study was aimed at evaluating the efficacy of modafinil in the treatment of patients with MA dependence.Methods: A randomized parallel controlled trial study was designed to compare the effectiveness of take-home, self-administered modafinil treatment in the intervention group and the controlled group in three months. The primary outcome measurements were severity and duration of craving, and selfreported methamphetamine consumption, as confirmed by urine drug test.Results: The relapse rate was 40 and 75 % in the intervention and controlled groups, respectively, indicating a decrease in relapse rate of MA in the intervention group (p < 0.05). During the three months, the severity and the duration of drug abuse craving in the intervention group were less than in the controlled group. Patients in the intervention group experienced an increase in retention rate and a decrease in slip rate (p < 0.05)Conclusion: The use of modafinil is not only effective on craving and relapse reduction, but also changes urine drug screens of patients with MA dependence to negative. Thus, modafinil is safely indicated as an effective medication to reduce withdrawal symptoms and the craving of patients with MA dependence

Expression of NMDA receptor subunits in human blood lymphocytes: A peripheral biomarker in online computer game addiction

Background and aims Repeated performance of some behaviors such as playing computer games could result in addiction. The NMDA receptor is critically involved in the development of behavioral and drug addictions. It has been claimed that the expression level of neurotransmitter receptors in the brain may be reflected in peripheral blood lymphocytes (PBLs). Methods Here, using a real-time PCR method, we have investigated the mRNA expression of GluN2A, GluN2D, GluN3A, and GluN3B subunits of the NMDA receptor in PBLs of male online computer game addicts (n = 25) in comparison with normal subjects (n = 26). Results Expression levels of GluN2A, GluN2D, and GluN3B subunits were not statistically different between game addicts and the control group. However, the mRNA expression of the GluN3A subunit was downregulated in PBLs of game addicts. Discussion and conclusions Transcriptional levels of GluN2A and GluN2D subunits in online computer game addicts are similar to our previously reported data of opioid addiction and are not different from the control group. However, unlike our earlier finding of drug addiction, the mRNA expression levels of GluN3A and GluN3B subunits in PBLs of game addicts are reduced and unchanged, respectively, compared with control subjects. It seems that the downregulated state of the GluN3A subunit of NMDA receptor in online computer game addicts is a finding that deserves more studies in the future to see whether it can serve as a peripheral biomarker in addiction studies, where the researcher wants to rule out the confusing effects of abused drugs

Association of SHANK3 Gene Polymorphism and Parkinson Disease in the North of Iran

Introduction: Parkinson Disease (PD), the second most common chronic neurodegenerative disorder, is characterized by tremor, bradykinesia, rigidity, and postural instability. SHANK3 (SH3 and multiple ankyrin repeat domain 3) belongs to the extremely conserved ProSAP/ Shank family of synaptic scaffolding proteins. Meanwhile, rs9616915 is a non-synonymous SNP (T>C) located in the exon 6 of the SHANK3 gene, which induces substitution of isoleucine to threonine and affects the function of the resulted protein. The present study aimed to evaluate whether rs9616915 polymorphism of SHANK3 is involved in the susceptibility to PD. Methods: The study subjects were 100 patients diagnosed with PD and 100 control volunteers. The obtained samples were evaluated by the polymerase chain reaction-restriction fragment length polymorphism method. Results: A significant association was found in genotype distribution between cases and controls. Individuals with TC genotype had increased risk of PD (P=0.035, OR=1.98, 95% CI=1.04 - 3.74). No significant difference was found in allele distribution (P=0.7). Conclusion: The findings suggest that the SHANK3 rs9616915 polymorphism is associated with an increased risk of PD in the population. Further studies are needed to confirm the role of the SHANK3 gene in PD

The Role of Protein Kinase B Signaling Pathway in Anti-cancer Effect of Rolipram on Glioblastoma Multiforme: An In Vitro Study

Introduction: The mechanism of putative cytotoxicity of 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone (rolipram), a specific phosphodiesterase-4 (PDE4) inhibitor, on glioblastoma multiforme (GBM) is almost unknown. This study aimed to investigate the role of protein kinase B (Akt) pathway in the cytotoxic effect of rolipram on human GBM U87 MG cell line and tumor-initiating cells (TICs) isolated from patient's GBM specimen. Methods: TICs were characterized by using flow cytometry and quantitative real-time PCR. The cells were treated with rolipram at inhibitory concentration of 50% (IC50) in the presence or absence of SC79 (4µg/mL), a specific AKT activator, for 48 hours. The cell viability and apoptosis were measured by MTT assay and TUNEL staining, respectively. The relative expression of Phospho-Akt (Ser473), matrix metalloproteinase 2 (MMP2), and vascular endothelial growth factor A (VEGFA) were detected using Western blotting. Results: The findings showed that rolipram could suppress cell viability in both U87MG and TICs, dose-dependently. Interestingly, the rolipram-induced cytotoxicity was significantly reduced in the presence of SC79. Nevertheless, in rolipram-treated cells, the pretreatment with SC79 significantly led to increase in U87 MG cells and TICs apoptosis and decrease in viability of U87 MG cells but not TICs relative to corresponding control. In U87 MG and TICs, rolipram-induced reduction of Phospho-Akt (Ser473) and MMP2 levels were significantly suppressed by SC79. Conclusion: There is a cell type-specific mechanism of anti-proliferative action of rolipram on GBM cells. The reduction of intracellular level of MMP2 but not VEGFA by rolipram is conducted through the inhibition of Akt signal. Rolipram-induced apoptosis is mediated via Akt dependent/independent mechanisms

X Chromosome Inactivation in Opioid Addicted Women

Introduction: X chromosome inactivation (XCI) is a process during which one of the two X chromosomes in female human is silenced leading to equal gene expression with males who have only one X chromosome. Here we have investigated XCI ratio in females with opioid addiction to see whether XCI skewness in women could be a risk factor for opioid addiction. Methods: 30 adult females meeting DSM IV criteria for opioid addiction and 30 control females with no known history of addiction were included in the study. Digested and undigested DNA samples which were extracted from blood were analyzed after amplification of the polymorphic androgen receptor (AR) gene located on the X chromosome. XCI skewness was studied in 3 ranges: 50:50–64:36 (random inactivation), 65:35–80:20 (moderately skewed) and >80:20 (highly skewed). Results: XCI from informative females in control group was 63% (N=19) random, 27% (N=8) moderately skewed and 10% (N=3) highly skewed. Addicted women showed 57%, 23% and 20%, respectively. The distribution and frequency of XCI status in women with opioid addiction was not significantly different from control group (P=0.55). Discussion: Our data did not approve our hypothesis of increased XCI skewness among women with opioid addiction or unbalanced (non-random) expression of genes associated with X chromosome in female opioid addicted subjects

Mu Opioid Receptor Gene: New Point Mutations in Opioid Addicts

Introduction: Association between single-nucleotide polymorphisms (SNPs) in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction.  Methods: 79 opioid-dependent subjects (55 males, 24 females) and 134 non-addict or control individuals (74 males, 60 females) participated in the study. Genomic DNA was extracted from volunteers’ peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR) whose products were then sequenced.  Results: Three different heterozygote polymorphisms were observed in 3 male individuals: 759T>C and 877G>A mutations were found in 2 control volunteers and 1043G>C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant.  Discussion: It seems that the sample size used in our study is not enough to confirm or reject any association between 759T>C, 877G>A and 1043G>C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population

Morphine Exposure and Enhanced Depression-like Behaviour Confronting Chronic Stress in Adult Male Offspring Rat

Introduction: Opioid addiction is an important concern in the World. Reports demonstrate that substance use disorder could influence genetic and environmental factors, and children of addicts have a higher rate of psychopathology. In this study, we investigated depression-like behavior among offspring of morphine-exposed rat parents.  Methods: Adult male and female Wistar rats received morphine for 21 consecutive days and then let them were free of drugs for ten days. Offspring of these rats were divided into three distinct groups: maternal morphine-exposed, paternal morphine-exposed, and both maternal and paternal morphine-exposed. We used sucrose preference and Forced Swim Test (FST) to measure depression-like behavior. Also, we induced chronic mild stress using repeated corticosterone injection and evaluated depression-like behavior in offspring of morphine-exposed parents compared with offspring of healthy ones.  Results: Results indicated that depression-like behaviors in the offspring of morphine-exposed rats were higher than those in the offspring of the control group in confronting with chronic mild stress. Additionally, mild chronic stress can produce an exaggerated effect on depression-like behavior in offspring of the morphine-exposed parent(s) compared with those of the control group.  Conclusion: Our data support the previous hypothesis that the depression rate is higher in the children of addicts. We verified that even when mother or father was clean of opioid in the time of gestation, their children would be susceptible to depression. Dysregulation of hypothalamic-pituitary-adrenal axis and changing in neuronal features in the hippocampus increased depression-like behavior in the offspring of morphine-exposure parents

Transplantation of Adipose Tissue-Derived Stem Cells into Brain Through Cerebrospinal Fluid in Rat Models: Protocol Development and Initial Outcome Data

Background: Cell therapy is an important strategy for the treatment of incurable diseases including those that occur in the Central Nervous System (CNS). Among different strategies, the method of delivering or transplantation of cells into the brain has shown significant effects on regeneration. In this study, a new protocol has been developed for the transplantation of adipose tissuederived stem cells into the brain through Cerebrospinal Fluid (CSF) in rat models. Methods: For this purpose, a wide range of ages (7-30 days old) of male neonates of Wistar rats was used. Moreover, human adipose tissue was obtained from a superficial layer of abdomen through liposuction surgery. The size of the inserted part of needle to access middle cranial fossa and subarachnoid space in animals with an average weight of 10-80 g was determined. In addition, to confirm the entrance of needle into the subarachnoid space, CSF was aspirated slowly and then injection was done within two minutes. Results: The findings showed the presence of transplanted human Adipose-Derived Stem Cells (hADSC) in the cerebellum and basal ganglia following three days and also after two months that confirmed the entrance of transplanted cells into the cerebrospinal fluid and migration of them into the brain tissue. All the animals survived after the transplantation process, with the lowest side effects compared to the available conventional methods. Conclusion: It can be concluded that the cells could be efficiently transplanted into CSF through subarachnoid space by injection via superior orbital fissure with a minimally invasive techniqu