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1.
GREGOR HASLER 《World psychiatry》2010,9(3):155-161
Due to the clinical and etiological heterogeneity of major depressive disorder,it has been difficult to elucidate its pathophysiology. Current neurobiologicaltheories with the most valid empirical foundation and the highest clinicalrelevance are reviewed with respect to their strengths and weaknesses. Theselected theories are based on studies investigating psychosocial stress andstress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine,glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophicfactors, and circadian rhythms. Because all theories of depression apply toonly some types of depressed patients but not others, and because depressivepathophysiology may vary considerably across the course of illness, the currentextant knowledge argues against a unified hypothesis of depression. As a consequence,antidepressant treatments, including psychological and biological approaches,should be tailored for individual patients and disease states. Individualdepression hypotheses based on neurobiological knowledge are discussed interms of their interest to both clinicians in daily practice and clinicalresearchers developing novel therapies. 相似文献
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Identifying neurobiological mechanisms mediating the emergence of individual differences in behavior is critical for advancing our understanding of relative risk for psychopathology. Neuroreceptor positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can be used to assay in vivo regional brain chemistry and function, respectively. Typically, these neuroimaging modalities are implemented independently despite the capacity for integrated data sets to offer unique insight into molecular mechanisms associated with brain function. Through examples from the serotonin and dopamine system and its effects on threat- and reward-related brain function, we review evidence for how such a multimodal neuroimaging strategy can be successfully implemented. Furthermore, we discuss how multimodal PET-fMRI can be integrated with techniques such as imaging genetics, pharmacological challenge paradigms and gene-environment interaction models to more completely map biological pathways mediating individual differences in behavior and related risk for psychopathology and inform the development of novel therapeutic targets. 相似文献
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Sookoian S Gemma C García SI Gianotti TF Dieuzeide G Roussos A Tonietti M Trifone L Kanevsky D González CD Pirola CJ 《Obesity (Silver Spring, Md.)》2007,15(2):271-276
Obesity and hypertension are increasing medical problems in adolescents. Serotonin transporter (5-HTT) is involved in mood and eating disturbances. Encoded by the gene SLC6A4, the promoter shows functional insertion/deletion alleles: long (L) and short (S). Because individuals who are carriers for the short version are known to be at risk for higher levels of anxiety, we hypothesized that this variant may be associated with overweight. Data and blood samples were collected from 172 adolescents out of a cross-sectional, population-based study of 934 high school students. To replicate the findings, we also included 119 outpatients from the Nutrition and Diabetes Section of the Children's County Hospital. We found that the S allele was associated with overweight (BMI > 85th percentile), being a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85; 95% confidence interval (CI): 1.13, 3.05; p < 0.02]. Additionally, in the outpatient study, compared with the homozygous LL subjects, S allele carriers showed a higher BMI z-score (1.47 +/- 1.09 vs. 0.51 +/- 1.4; p < 0.002) and were more frequent in overweight children. In conclusion, the S allele of the SLC6A4 promoter variant is associated with overweight being an independent genetic risk factor for obesity. 相似文献
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Bryon Adinoff Michael D. Devous Mark J. Williams Thomas S. Harris Susan E. Best Hongyun Dong Tanya Zielinski 《Addiction biology》2014,19(2):250-261
5‐hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self‐administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early‐onset, but not late‐onset, alcohol‐dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment‐seeking cocaine‐addicted and 22 sex‐, age‐ and race‐matched healthy control participants. Differences between early‐ (first use before 20 years, n = 10) and late‐onset (first use after 20 years, n = 10) cocaine‐addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine‐addicted and control participants were observed following ondansetron relative to saline. Early‐onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late‐onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early‐onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late‐onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine‐addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol‐dependent patients. 相似文献
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The serotonin system underlies a wide variety of behavioral traits and its dysregulation is the cause of numerous neuropsychiatric disorders. Among genes involved in the system, the serotonin transporter (SERT) is integral and has been repeatedly shown to be associated with disease as well as being a primary drug target. In addition to promoter region variation, we identify here variation in a regulatory region in the 3' untranslated region (UTR) of the SERT gene in both humans and rhesus macaques. We comprehensively survey the 3' UTR of SLC6A4 in Indian-origin rhesus macaques to identify three single nucleotide polymorphisms (SNPs) creating two haplotypes, both derived from an ancestral sequence, that represent the vast majority of the alleles in the population. Through the use of a luciferase reporter gene assay, we are able to show that not only do these alleles have differential effects on gene expression, modulated through changes in messenger RNA stability, but that different commonly occurring SNPs in the human 3' UTR also have similar effects. This finding not only offers additional insight into the regulation, and thus dysregulation, of SERT expression, but also suggests the role of natural selection in maintaining both high and low SERT expression levels broadly across populations of multiple primate species. 相似文献
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中国人群5—羟色胺2A受体基因中T102C多态性与精神分裂症的联系 总被引：3，自引：1，他引：3
在研究５－羟色胺２Ａ受体基因多态性与精神分裂症的关联分析中,调查了２０２例精神分裂症患者及２０２例正常对照。各相匹配组间比较未发现基因型和等位基因频率的显著性差异。结果提示,在中国人群中５－羟色胺２Ａ受体的静态Ｔ１０２Ｃ突变与精神分裂症之间不存在关联。 相似文献
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The individual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, among other things, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed in several tests. The T102C and A1438G polymorphisms were associated with variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on the Hypomania scale, and a lower score on the Social Introversion scale and were assumed to have higher activity and sociability. Carriers of A1438G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on the No Close Friends scale, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of 5HTR2A proved to be associated with personality traits in mentally healthy people. 相似文献
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Aryeh I. Herman Tamlin S. Conner Raymond F. Anton Joel Gelernter Henry R. Kranzler Jonathan Covault 《Addiction biology》2011,16(1):124-132
The present study examined the association between a measure of sociopathy and 5‐HTTLPR genotype in a sample of individuals from Project MATCH, a multi‐center alcohol treatment trial. 5‐HTTLPR, an insertion–deletion polymorphism in SLC6A4, the gene encoding the serotonin transporter protein, results in functionally distinct long (L) and short (S) alleles. The S allele has been associated with a variety of psychiatric disorders and symptoms including alcohol dependence, but it is unknown whether 5‐HTTLPR increases the risk for co‐morbid sociopathy among those with alcohol dependence. Eight hundred sixty‐two subjects diagnosed with alcohol dependence completed the California Psychological Inventory, a psychological assessment that includes a measure of socialization, which was used as a proxy measure of sociopathy. Subjects were genotyped for the insertion–deletion polymorphism, as well as a single nucleotide polymorphism (A→G) that is located in the inserted region. Regression analysis revealed that after controlling for age, which was negatively related to socialization score, 5‐HTTLPR genotype interacted with sex to determine socialization score (P < 0.001). Males with the L'L' genotype (i.e. those homozygous for the LA allele) had lower socialization scores (i.e. greater sociopathy) than males who were carriers of the S' allele (P = 0.03). In contrast, women with the S'S' genotype had lower socialization scores than women with two L' alleles (P = 0.002) and tended to have lower Socialization Index of the California Psychological Inventory scores than women with one copy of the L' allele (P = 0.07). Among individuals with alcohol use disorders, the tri‐allelic 5‐HTTLPR polymorphism had opposite effects on socialization scores in men than women. The basis for this finding is unknown, but it may have implications for sub‐typing alcoholics. 相似文献
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V. E. Golimbet 《Molecular Biology》2008,42(5):738-746
Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenic patients. However, the role of specific genes in the development of cognitive deficit remains elusive. The review considers the current studies on the association between gene polymorphisms and cognitive dysfunction in schizophrenics. Main attention is drawn to the consistently reproducible association between the COMT polymorphism Val158Met and cognitive traits, which has a biological and neuropsychological support. The association studies with the genes for the dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase, and D-amino acid oxidase activator are reviewed as well. 相似文献
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云南汉族人群5-羟色胺转运体基因启动子区多态性与酒精依赖的相关性 总被引：1，自引：0，他引：1
为了探讨云南汉族人群中5-羟色胺转运体基因启动子区多态性(5-HTTLPR)与酒精依赖的关联性, 文章采用PCR扩增和DNA测序技术, 对云南地区118例酒精依赖患者和214例健康对照个体进行了5-HTTLPR的基因多态性分析。结果表明: 酒精依赖患者组和正常对照组的5-HTTLPR的基因型分布存在显著性差异, L/L和L/S基因的携带者人群嗜酒发生率显著低于S/S基因型人群(OR: 0.581, P=0.026)。S和L等位基因频率在两组间无统计学差异(χ2=2.594, P=0.107), 但其分布存在种族差异性。因此, 云南地区人群中5-HTTLPR多态与酒精依赖存在相关性, L/L和L/S基因型可能是降低酒精依赖发病的影响因子之一。 相似文献
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The review considers the most interesting data on the molecular genetic basis of mental disorders and personality traits, which were obtained within the framework of the Russian program Human Genome. Polymorphic markers Taq1A of the dopamine receptor gene and T102C of the serotonin receptor type 2A gene were associated with schizophrenia, in particular, chronic forms with poor prognosis. In mentally health people, the insertion/deletion polymorphism of the serotonin transporter gene was associated with schizoid traits. 相似文献
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D. A. Nielsen M. J. Harding S. C. Hamon W. Huang T. R. Kosten 《Genes, Brain & Behavior》2012,11(8):1001-1008
Disulfiram is a cocaine pharmacotherapy that may act through increasing serotonin, benefiting patients with genetically low serotonin transporter levels (5‐HTTLPR, S′ allele carriers) and low serotonin synthesis (TPH2, A allele carriers). We stabilized 71 cocaine and opioid co‐dependent patients on methadone for 2 weeks and randomized them into disulfiram and placebo groups for 10 weeks. We genotyped the SLC6A4 5‐HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating disulfiram treatment for cocaine dependence. Cocaine‐positive urines dropped from 78% to 54% for the disulfiram group and from 77% to 76% for the placebo group among the 5‐HTTLPR S′ allele carriers (F = 16.2; df = 1,301; P < 0.0001). TPH2 A allele carriers responded better to disulfiram than placebo (F = 16.0; df = 1,223; P < 0.0001). Patients with both an S′ allele and a TPH2 A allele reduced cocaine urines from 71% to 53% on disulfiram and had no change on placebo (F = 21.6; df = 1,185; P < 0.00001). 相似文献
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Objective: There is considerable evidence that cortisol secretion is associated with obesity. The regulation of the 5‐hydroxytryptamine receptor 2A (5‐HT2A) gene might play an essential role because it is involved in the control of cortisol secretion. Therefore, we examined the potential impact of the 5‐HT2A ?1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. Research Methods and Procedures: The subjects were genotyped by using polymerase chain reaction amplification of the promoter region of the gene for 5‐HT2A followed by digestion of the reaction product with the restriction enzyme MspI. Results: The frequencies were 0.39 for allele ?1438A and 0.61 for allele ?1438G. Homozygotes for the ?1438G allele had, in comparison with ?1438A/A subjects, higher body mass index, waist‐to‐hip ratio, and abdominal sagittal diameter. Moreover, cortisol escape from 0.25‐mg dexamethasone suppression was found in subjects with the ?1438A/G genotype. Serum leptin, fasting insulin, and glucose, as well as serum lipids, were not different across the ?1438G/A genotype groups. Discussion: From these results, we suggest the possibility that an abnormal production rate of the 5‐HT2A gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin‐hypothalamic‐pituitary‐adrenal system in those with genetic vulnerability in the serotonin receptor gene. 相似文献
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Golimbet V. E. Alfimova M. V. Shcherbatykh T. V. Abramova L. I. Kaleda V. G. Rogaev E. I. 《Molecular Biology》2001,35(3):336-338
Some studies associate the insertion/deletion polymorphism of the serotonin transporter (5-HTT) gene with anxiety-related personality traits in mentally healthy people, the short (s) allele being associated with a higher neuroticism score. The 5-HTT genotype and neuroticism score were established for 114 affective patients, 87 healthy relatives of endogenous psychosis patients, and for 156 mentally healthy people without familial psychiatric history. The effects of sex and age on the association between the two parameters was studied. Neuroticism proved to be not associated with the 5-HTT genotype. 相似文献
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慢性温和应激抑郁模型大鼠5-羟色胺、色氨酸和应激激素的变化 总被引：4，自引：0，他引：4
目的：通过观察慢性温和应激对大鼠行为及5-羟色胺、色氨酸、应激激素的影响,进一步阐明应激致抑郁发生的机制。方法：利用慢性不可预计温和应激（CUMS）结合行为学指标建立大鼠抑郁动物模型;高效液相检测血浆和脑5-HT、儿荼酚胺;放免方法检测血浆皮质醇换算成皮质酮含量;氨基酸分析仪检测血清色氨酸的含量。结果：①CUMS诱导8周大鼠糖水偏爱性与对照组相比明显减低（P〈0．05）;体重和旷场实验评分下降（P〈0．05）。②CUMS诱导8周大鼠大脑和血浆5-HT含量显著下降（P〈0．05）;而血清色氨酸含量与对照组相比则明显升高（P〈0．05）。③CUMS诱导8周大鼠血浆去甲肾上腺素和肾上腺素含量与对照组相比明显升高（P〈0．05）：血浆皮质酮含量与对照组相比统计学上无显著性差异（P〉0．05）。结论：利用CUMS建立的抑郁模型大鼠存在着神经内分泌紊乱,CUMS大鼠抑郁样行为的发生可能与血浆去甲肾上腺素和肾上腺素升高对色氨酸代谢的影响有关。 相似文献
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B. Ferguson J. E. Hunter J. Luty S. L. Street A. Woodall K. A. Grant 《Genes, Brain & Behavior》2012,11(8):949-957
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post‐traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from ?21% to 66%. Thirty‐seven monkeys from the high and low ends of the ACTH suppression distribution (18 ‘high’ and 19 ‘low’ animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH‐2610C>T, rhTPH2 2051A>C and rh5‐HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the ‘risk’ genotypes from these three loci was detected, with an increasing number of ‘risk’ genotypes associated with a blunted ACTH response (P = 0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone. 相似文献
19.
Hummerich R Reischl G Ehrlichmann W Machulla HJ Heinz A Schloss P 《Journal of neurochemistry》2004,90(5):1218-1226
The efficiency of serotonergic signal transduction is controlled by the density of serotonegic synapses and by the activity of the serotonin transporter (SERT), which selectively clears the synaptic cleft of the neurotransmitter. SERT is located in axons, where it is concentrated in varicosities and terminal boutons and thus is an exquisite marker for serotonergic synapses. This finding has been taken advantage of for neuroimaging serotonergic synaptic contact sites. Previous positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies were often carried out using radioligands that bind with high affinity to SERTs in the brainstem but also exhibit high affinity for dopamine and norepinephrine transporters and therefore did not allow quantification of serotonergic innervations in brain regions also containing dopaminergic or noradrenergic terminals. In order to visualize SERT availability more selectively, in recent years new tracers have been developed, one of which is [11C]DASB (N,N-dimethyl-2-2-amino-4-cyanophenylthiobenzylamine). Here, we have performed a detailed pharmacological characterization of unlabelled as well as radioactive DASB on recombinant human monoamine transporter proteins. Our results show that DASB selectively binds to SERT with high affinity (KD = 3.5 nm) to a site distinct from the serotonin (5-HT) recognition/translocation site. 5-HT inhibits DASB binding to SERT with more than one order of magnitude lower affinity than that of DASB binding (IC50 = 82.4 nm). These findings suggest DASB to be a highly selective PET tracer to visualize the density of serotonergic synapses in human brain. 相似文献
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ESTERINA PASCALE MARCO LUCARELLI FRANCESCA PASSARELLI RICHARD H. BUTLER ANDREA TAMELLINI ELSA ADDESSI ELISABETTA VISALBERGHI ARIANNA MANCIOCCO AUGUSTO VITALE GIOVANNI LAVIOLA 《American journal of primatology》2012,74(11):1028-1034
Genetic variation in the human serotonin system has long been studied because of its functional consequences and links to various neuropsychiatric and behavior‐related disorders. Among non‐human primates, the common marmosets (Callithrix jacchus) and tufted capuchins monkeys (Cebus apella) are becoming increasingly used as models to study the effects of genes, environments, and their interaction on physiology and complex behavior. In order to investigate the independent functions of and potential interactions between serotonin‐related genes, anxiety and neuropsychiatric disorders, we analyzed the presence and variability of the serotonin transporter gene‐linked polymorphic region (5‐HTTLPR) in marmoset and capuchin monkeys. By PCR and using heterologous primers from the human sequence, we amplified and then sequenced the corresponding 5‐HTT region in marmosets and capuchins. The resulting data revealed the presence of a tandem repeat sequence similar to that described in humans, but unlike humans and other Old World primates, no variable length alleles were detected in these New World monkeys, suggesting that if serotonin transporter is involved in modulating behavior in these animals it does so through different molecular mechanisms. Am. J. Primatol. 74:1028‐1034, 2012. © 2012 Wiley Periodicals, Inc. 相似文献