Association study between T-182C and G1287A polymorphisms in norepinephrine transporter gene and schizophrenia / 中华行为医学与脑科学杂志

Objective To explore whether the norepinephrine transporter(NET) gene T-182C and G1287A polymorphisms are involved in the etiology of schizophrenics among the Chinese Han population.Methods 249 schizophrenics(case group) and 309 healthy physical examiners(control group) of the Chinese Han population were collected.Ligase detection reaction was used to detect the genotype distributions and allele frequencies of NET rs2242446 and rs5569 polymorphisms in the two groups.The genotype distributions and allele frequencies of these two single nucleotide polymorphisms (SNPs) were also compared in the case and control groups.Results In the case group,the TF genotype of the NET gene loci rs2242446 was the most,48.6％,and the CC genotype of which was the least,8.4％.In the control group,the CT genotype was the most,47.9％,and the C C genotype was the least,11.3％,the minimum allele frequency was 29.9％.In the case group,the GG genotype of the NET gene loci rs5569 was the most,46.2％,and the CC genotype was the least,9.6％.In the control group,GG genotype was the most,51.5％,and the AA genotype was the least,10.3％,and the minimum allele frequency was 29.4％.No significant differences in the genotype and allele distribution of NET rs2242446 and rs5569 were found in Chinese-Han patients with schizophrenia and control participants (all P＞ 0.05).In gender-specific analyses,similarly,no significant differences were found for rs2242446 and rs5569 genotype and allele distributions in either the male or the female case-control comparisons (all P＞ 0.05).Conclusion The NET rs2242446 and rs5569 polymorphisms are not associated with schizophrenia in Chinese Han population.

Improvement of NET and 5-HTT expression involved in the anti-depressive effect of valproate / 中国药科大学学报

@#This study aimed at investigating the correlations between antidepressive effect of valproate and improvements of NET and 5-HTT expression in depressive rats leaded by chronic mild unpredicted stress(CUMS)with solitary condition. Sixty male SD rats were divided into normal group(NG), model group(MG), valproate treated-normal group(VNG), and valproate treated-model group(VMG), randomly. The changes of depressive behaviors were evaluated by the open-field test and force swimming test. The contents of MDA, activities of SOD and CAT in serum, the mRNA and protein expression of NET, 5-HTT in hippocampus were determined by biochemical methods, Real-time PCR and Western Blot, respectively. Results showed that CUMS can significantly decrease the activities in open-field test, SOD and CAT activities in serum, expression of 5-HTT in hippocampus, and obviously increase the immobility time in force swimming test, the level of MDA and expression of NET. The treatment of valproate obviously improved the changes induced by CUMS. However, the treatment of valproate had no significant influences on behaviors of NG rats. So, it revealed that improvements of the mRNA and protein expression of NET, 5-HTT may be involved in the antidepressive effect of valproate.

Influence and interaction of genetic polymorphisms in norepinephrine transporter and enviroment on antidepressant drug response / 中华行为医学与脑科学杂志

Objective To determine how genetic polymorphisms in norepinephrine transporter (NET) gene influence the response of antidepressant treatment and how they interact with childhood trauma and recent life stress in a Chinese depressive patients.Methods 281 Chinese Han depressive patients received single antidepressant drugs for 6 weeks.Hamilton Depression Scale-17 (HAMD-17),the Childhood Trauma Questionnaire short term (CTQ-SF) and the Life Events Scale (LES) were used to evaluate severity of depressive symptoms and the occurrence of stressful life events respectively.Three single nucleotide polymorphisms (SNPs) in norepinephrine transporter were genotyped.Associations of single locus and haplotypes with antidepressant treatment response were analyzed using UNPHASED 3.0.13.The interaction of gene and life stress was analyzed by SPSS13.0 software.Results One NET SNP rs2242446 was significantly associated with antidepressant response in this Chinese male sample(0.4118vs0.2375,x2=7.046,P=0.0079,OR=0.445,95％ CI (0.243-0.815)),as was the haplotype CG(rs2242446 and rs5569;x2 =5.886,P=0.0153,OR=0.457,95％ CI (0.198-1.054)) and another haplotype CG-G(rs2242446,rs1532701 and rs5569;x2=5.360,P=0.0206,OR=0.530,95％ CI (0.202-1.386)) of NET in male samples.The NET SNPs rs5569 demonstrated interaction with childhood trauma to influence antidepressant response(β=-2.727,SE =1.195,P=0.023,OR=0.065,95％ CI (0.006-0.681)).Conclusion Antidepressant drug response was influenced by not only NET genetic polymorphisms in norepinephrine transporter gene but also interaction between the NET genetic polymorphisms and early life stress.

Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

OBJECTIVE: Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model. METHODS: After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students. RESULTS: A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms. CONCLUSION: We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.

Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study

OBJECTIVE: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. METHODS: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. RESULTS: No subjects reporting abuse with high impact in adulthood (IES-15 > or =26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. CONCLUSION: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.

Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring

A substantial proportion of patients with autism spectrum disorder (ASD) display hyperactivity as a comorbid symptom. Exposure to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.

The relationship of violent behavior with polymorphism of norepinephrine transporter gene, childhood abuse and their interaction effect in male adolescents / 中华行为医学与脑科学杂志

Objective To explore the relationship between the rs3785143 polymorphism of norepinephrine transporter gene,and investigate the influence of interaction effect between NET gene polymorphism and childhood abuse in adolescents with violent behavior.Methods Adolescent male offenders were divided into violent group (124 samples) and nonviolent group (120 samples).The rs3785143 polymorphisms of NET gene were measured by used SNaPshot SNP technology in 244 samples.Chi-square test was used to compare the distribution difference between three groups of each gene type and the allele frequency distribution.Results ①There was no statistically significant difference among violent group and nonviolent group in the genotype and allele frequencies of rs3785143 polymorphism (x2=0.753,0.022; all P＞0.05).②64.5％ violent adolescents have experience of childhood abuse,and 35.5％ had no history of abuse ;48.3％ nonviolent adolescents have experience of childhood abuse,and 51.7％ had no history of abuse(x2=6.50,P＜0.05).③There was not significant interaction between NET gene polymorphism and childhood abuse((OR=0.386,P＞0.05) 95％ CI (0.457-4.739)).Conclusions The NET gene polymorphism is not associated with violent behavior in male adolescents,and there was not interaction between NET gene polymorphism and childhood abuse.

Altered expression of norepinephrine transporter and norepinephrine in human placenta cause pre-eclampsia through regulated trophoblast invasion / 대한생식의학회지

OBJECTIVE: We investigated the norepinephrine transporter (NET) expression in normal and pre-eclamptic placentas and analyzed the invasion activity of trophoblastic cells based on norepinephrine (NE)-NET regulation. METHODS: NET and NE expression levels were examined by western blot and enzyme-linked immunosorbent assay, respectively. Trophoblast invasion activity, depending on NE-NET regulation, was determined by NET-small interfering RNA (siRNA) and NET transfection into the human extravillous trophoblast cells with or without NE treatment and invasion rates were analyzed by zymography and an invasion assay. RESULTS: NET mRNA was expressed at a low level in pre-eclamptic placentas compared with normal placentas and NE concentration in maternal plasma increased significantly in pre-eclamptic women compared to normal pregnant women (p<0.05). NET gene upregulation and NE treatment stimulated trophoblast cell invasion up to 2.5-fold (p<0.05) by stimulating matrix metalloproteinase-9 activity via the phosphoinositol-3-kinase/AKT signaling pathway, whereas NET-siRNA with NE treatment reduced invasion rates. CONCLUSION: NET expression is reduced by inadequate regulation of NE levels during placental development. This suggests that a complementary balance between NET and NE regulates trophoblast cell invasion activities during placental development.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Central Nervous System Drug Evaluation Using Positron Emission Tomography

In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET.

An Association Study between Various Monoamine Transporter Gene Polymorphisms and Treatment Response to Mirtazapine in Major Depression / 대한정신약물학회지

OBJECTIVE: Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of various monoamine transporter genetic polymorphisms with treatment response to mirtazapine in major depressive patients in elderly. METHODS: In this study, three genetic polymorphisms were selected: serotonin transporter 5- HTTLPR, serotonin transporter 5-HTT intron 2 VNTR, and norepinephrine transporter NET (G1287A). The patients with major depression diagnosed by DSM-IV were recruited to a 6 week naturalistic mirtazapine treatment study in Samsung Medical Center. Treatment response to mirtazapine was defined as > or =50% decrease in HAMD-17 scores at 6 weeks, and the genotypes in the patients were determined using the polymerase chain reaction. RESULTS: Our results showed that ss allele carriers were included more in responder group (ss allele in responder vs. non responder group; 69.4% vs. 40.0%). In addition, l-allele (sl/ll) carriers were included less in responder group (sl/ll allele in responder vs. non responder group; 30.6% vs. 60.0%). Multiple logistic regression analyses showed the 5-HTTLPR polymorphism as an predictor of the mirtazapine response (5HTTLPR ss allele carrier vs. l-allele (sl/ll) carrier; odds ratio: 3.81; 95% confidence interval [CI], 1.32-11.0; p=0.013). However, 5-HTT intron 2 VNTR l/s (p=0.33 by multiple logistic regression; [OR], 0.53; 95% [CI], 0.15-1.88), and NET (G1287A) G/A (p=0.68 by multiple logistic regression; [OR], 1.25; 95% [CI], 0.44-3.53) showed no statistical significant influences on response rate. CONCLUSION: In conclusion, 5HTTLPR polymorphism may predict treatment response to mirtazapine in major depressive patients in elderly.