Motivation for treatment preceding and following a substance abuse program

BACKGROUND: Motivation for treatment is generally considered a powerful predictor of treatment seeking and success in patients with alcohol and drug dependence disorders. Objective measures have seldom been used, however, to assess how motivation is altered during treatment, or the impact of depression/anxiety on motivation. METHODS: We assessed motivation using the Treatment Motivation Questionnaire (TMQ) in 78 male alcohol- and drug-dependent veterans immediately preceding and following an intensive, 2-week residential substance abuse program. The TMQ assesses four domains of motivation: internal motivation, external motivation, interpersonal help-seeking, and nonconfidence in treatment. RESULTS: Following treatment, only external motivation changed (decreased), whereas the other dimensions of motivation retained the high levels observed pretreatment. Depression (as measured by the Beck Depression Inventory, BDI) was highly correlated with three of the four domains of motivation, while anxiety (as measured by the Spielberger State-Trait Anxiety Inventory, STAI) was highly correlated solely with internal motivation. CONCLUSIONS: Our findings suggest that depression and anxiety may differentially effect motivation and that external motivation may be quite transient; treatment implications of these findings are discussed. The usefulness of the TMQ in a residential population was also explored.     

Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders

G-protein-coupled receptor (GPCR)-mediated signalling is the most widely used signalling mechanism in cells, and its regulation is important for various physiological functions. The cannabinoid-1 (CB₁) receptor, a GPCR, has been shown to play a critical role in neural circuitries mediating motivation, mood and emotional behaviours. Several recent studies have indicated that impairment of CB₁ receptor-mediated signalling may play a critical role in the pathophysiology of various neuropsychiatric disorders. In this article, the authors briefly review literature relating to the role played by the endocannabinoid system in various neuropsychiatric disorders, and the CB₁ receptor as a potential therapeutic target for the treatment of alcoholism, depression, anxiety and schizophrenia.     

Blood microRNA changes in depressed patients during antidepressant treatment

MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram. Thirty miRNAs were differentially expressed after the AD treatment: 28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated. miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand–receptor interaction, axon guidance, long-term potentiation and depression), supporting the hypothesis that the differentially regulated miRNAs may be involved in the AD mechanism.     

Shared changes in gene expression in frontal cortex of four genetically modified mouse models of depression

This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of > 10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience.     

Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders

G-protein-coupled receptor (GPCR)-mediated signalling is the most widely used signalling mechanism in cells, and its regulation is important for various physiological functions. The cannabinoid-1 (CB(1)) receptor, a GPCR, has been shown to play a critical role in neural circuitries mediating motivation, mood and emotional behaviours. Several recent studies have indicated that impairment of CB(1) receptor-mediated signalling may play a critical role in the pathophysiology of various neuropsychiatric disorders. In this article, the authors briefly review literature relating to the role played by the endocannabinoid system in various neuropsychiatric disorders, and the CB(1) receptor as a potential therapeutic target for the treatment of alcoholism, depression, anxiety and schizophrenia.     

Raising the expectations of long-term treatment strategies in anxiety disorders

This article describes the long-term course of anxiety disorders based on the findings of the Harvard/Brown Anxiety Research Program (HARP) study--a prospective, naturalistic, longitudinal study of patients with anxiety disorders. Data from the HARP study emphasize both the chronicity of anxiety disorders and their frequent psychiatric comorbidity with other anxiety disorders and depression. Social phobia and generalized anxiety disorder are more chronic than panic disorder, although the latter has higher rates of relapse following recovery. Anxiety disorders have a major impact on the everyday lives of sufferers. The detrimental effects on social, psychological, and physical functioning are comparable with other chronic medical and psychiatric conditions, including diabetes, heart disease, and depression. Comorbidity with depression significantly increases the probability of suicide and is associated with poorer outcome. Findings from the HARP study have significant implications for treatment, which currently tends to focus on short-term outcomes. Future studies should emphasize the role of preventive pharmacotherapy to improve the long-term course of anxiety and to reduce its associated suffering, suicide, and occupational and social impairment.     

Genes differentially expressed in CB1 knockout mice: Involvement in the depressive-like phenotype

Recent hypotheses to explain the neurobiology of depression underline the role played by stress in mood disorders. The endocannabinoid system is one of the major physiological substrates involved in emotional responses and stress. Thus, mice lacking CB₁ receptor exhibit a depressive-like phenotype and an increased vulnerability to deleterious effects of stress. In order to identify possible molecular pathways contributing to this phenotype, we have examined the gene expression profile of mutants at basal conditions and after the exposure to repeated stress. Several genes coding for neurotransmitter receptors, neurotrophic factors, neuropeptides and hormones receptors were differentially expressed in CB₁ knockout mice.     

三种量表评价心房颤动患者焦虑抑郁的比较

目的 探讨心房颤动患者焦虑抑郁情绪的发生情况,以及医院焦虑抑郁自评量表（HADS）、Zung氏焦虑自评量表（SAS）抑郁自评量表（SDS）、汉密尔顿焦虑量表（HAMA）、抑郁量表（HAMD）评定焦虑抑郁的一致性和非精神心理专科医师判断心房颤动患者焦虑抑郁状态时对量表的选择.方法 入选心房颤动患者179例,分别采用HADS、SAS/SDS、HAMA/HAMD评定受试者的情绪情况,对患者焦虑抑郁评分、3种量表一致性及2种自评量表填写质量进行统计分析.结果 根据HADS的焦虑分量表（HADa）评分,心房颤动患者焦虑情绪阳性68例,占38.0％;根据HADS的抑制分量表（HADd）评分,抑郁情绪阳性86例,占48.0％ SAS评分焦虑情绪阳性71例,占39.7％;SDS评分抑有郁情绪阳性77例,占43.0％.HAMA评分焦虑情绪阳性65例,占36.3％;HAMD评分抑郁情绪阳性76例,占42.5％.3种量表评定一致性检验,HADa、SAS与HAMA Kappa值分别为0.438、0.337,HADd、SDS与HAMD Kappa值分别为0.416、0.395.结论 心房颤动患者常伴有焦虑或抑郁情绪;HADS与HAMA、HAMD具中等一致性,SAS、SDS与HAMA、HAMD具轻度一致性.HADS具有较好的有效性和实用性,更适于非精神专科对心房颤动患者焦虑抑郁情绪的筛查.     

抑制 BHK21细胞 STYK1/NOK基因的转录组分析 #br#

目的 转录组分析抑制丝氨酸-苏氨酸-酪氨酸激酶 1（STYK1/NOK）后仓鼠肾正常细胞 BHK21的基因表 达,并分析其可能作用的信号通路。方法 BHK21细胞分为空载体组（转染 6 µg空载体 pBs/U6）、低转染浓度组（2 µg si-STYK1/NOK质粒+4 µg空载体 pBs/U6）和高转染浓度组（6 µg si-STYK1/NOK质粒）。转染 48 h后,Western blot 检测 STYK1/NOK蛋白表达,基于检测结果,选取空载体组和高转染浓度组提取总 RNA进行转录组测序。将测序所 得的序列进行过滤比对,获得差异表达基因后,应用 R软件进行生物功能（GO）分析和 KEGG信号通路分析。应用 STRING蛋白质互作数据库中的互作关系进行差异基因蛋白互作网络的分析。采用 qRT-PCR验证关键差异表达基 因亚甲基四氢叶酸脱氢酶 2（Mthfd2）、转录激活因子 5（Atf5）,ⅡA分泌型磷脂酶 A2（Pla2g2a）、6-磷酸果糖-2-激酶/ 果糖-2,6-双磷酸酶 3（Pfkfb3）的表达。CCK-8法检测空载体组和高转染浓度组细胞增殖情况。结果 Western blot 结果表明高转染浓度组明显抑制 STYK1/NOK蛋白表达。高转染浓度组与空载体组相比,共发现差异表达基因 44 个,包括 19个上调基因和 25个下调基因。GO富集分析发现差异表达基因主要影响生物调控、细胞进程、代谢调控、 细胞生物过程、细胞、细胞部分、胞外区、配体和催化活性。KEGG通路分析发现差异表达基因主要集中作用于免疫 系统、癌症、细胞周期、信号转导和氨基酸代谢等方面。qRT-PCR结果表明,高转染浓度组Mthfd2、Atf5的相对表达量 显著上调（P＜0.05）,Pfkfb3、Pla2g2a的相对表达量显著下调（P＜0.05）,与测序结果相一致。细胞增殖实验表明高转 染浓度组细胞增殖明显高于空载体组（P＜0.01）。结论 抑制 BHK21细胞 STYK1/NOK表达后,致使 BHK21细胞原 癌基因表达增强,抑癌基因表达减少,促进细胞增殖。     

基于生物信息学筛选乙型肝炎差异表达基因及其在预测肝癌预后中的作用

目的:应用生物数据库及生物信息分析技术探索乙型肝炎病毒(HBV)感染肝细胞的差异表达基因,分析其在肝癌预后中的预测价值。方法:登录基因芯片公共数据库(GEO)下载数据并检测基因芯片品质,应用R软件甄选差异基因,富集分析对差异基因进行分类注释,构建蛋白质相互作用网络筛选核心基因,运用基因表达谱数据动态分析(GEPIA)验证核心差异表达基因,分析5年生存率。结果:合计1041个基因在乙型肝炎病毒感染肝细胞中存在表达差异,基因本体(GO)富集分析显示差异基因主要与细胞外间隙、胞外区、胞外外泌体、环氧化酶P450通路、受体结合相关。京都基因和基因组百科全书(KEGG)通路分析显示差异基因主要参与补体及凝血级联反应、糖酵解/糖异生、视黄醇代谢、过氧化物酶体增殖物激活受体(PPAR)信号通路、碳代谢、代谢途径、初级胆汁酸生物合成、癌症中的蛋白聚糖、胆汁分泌等信号通路。蛋白互作网络筛选出10个关键基因。GEPIA数据库验证结果显示其6个基因高表达于肝癌组织,而生存分析验证激肽原基因1(KNG1)高表达组肝癌患者5年生存率更高。结论:生物信息学技术能有效筛选HBV感染肝细胞中的核心差异基因,并具有预测肝癌预后的作用。     

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.     

Sensitization to the conditioned rewarding effects of morphine modulates gene expression in rat hippocampus

Opiates addiction is characterized by its long-term persistence. In order to study the enduring changes in long-term memory in hippocampus, a pivotal region for this process, we used suppression subtractive hybridization to compare hippocampal gene expression in morphine and saline-treated rats. Animals were subjected to an extended place preference paradigm consisting of four conditioning phases. Sensitization to the reinforcing effects of the drug occurred after three conditioning phases. After 25 days of treatment rats were euthanized and the complementary DNA (cDNA) from the hippocampus of morphine-dependent and saline-treated animals were then screened for differentially expressed cDNAs. The selected 177 clones were then subjected to a microarray procedure and 20 clones were found differentially regulated. The pattern of regulated genes suggests impairments in neurotransmitter release and the activation of neuroprotective pathways.     

海洛因依赖住院患者睡眠质量调查及相关因素分析

目的:分析和总结海洛因依赖患者住院期间匹兹堡睡眠质量指数特征。方獉法獉:135例海洛因依赖患者住院期间接受了匹兹堡睡眠质量指数问卷(Pittsburgh Sleep QualityIndex,PSQI)评估。结果:根据PSQI,135例海洛因依赖患者住院期间可能有睡眠障碍(PSQI总分≥8)的为96.30%(130例)。海洛因依赖住院患者的睡眠质量与抑郁情绪、吸毒年限呈正相关,与焦虑情绪、每次吸毒量无明显相关。结论:绝大多数海洛因依赖住院患者睡眠质量较差,多种因素(包括抑郁情绪和吸毒年限)与海洛因依赖住院患者睡眠质量相关。     

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has revealed an important role for these receptors in various disorders of the nervous system including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. In this study, we used microarray technology to examine changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days. Approximately 30 min following the final drug administration, rats were sacrificed and frontal cortices were then dissected and examined for changes in gene expression by cDNA microarray analysis. Changes in gene expression with p-values less than 0.01 were considered to be statistically significant. The expression of 63 genes was changed by both MPEP and MTEP, with 58 genes down-regulated and 5 genes up-regulated. Quantitative PCR verified the magnitude and direction of change in expression of 9 of these genes (r2=0.556, p=0.017). Pathway analysis revealed that many of the biological processes altered by repeated MPEP and MTEP treatment were related to ATP synthesis, hydrolase activity, and signaling pathways associated with mitogen-activated protein kinase (MAPK). Our results demonstrate diverse effects of MPEP and MTEP gene expression in the frontal cortex, and these results may help elucidate the mechanisms by which these compounds produce beneficial effects in animal models of various disorders of the central nervous system.     

亚洲人群肝细胞癌mRNA-miRNA表达谱整合分析挖掘疾病治疗靶点

目的通过整合数据库分析筛选出与亚洲人肝细胞癌(HCC)生存期相关微小RNA(miRNA),并探讨该miRNA潜在的生物学调控网络。方法利用癌症基因组图谱(TCGA)数据库获取亚洲人群HCC癌组织编码基因(mRNA)和miRNA表达量数据集,采用perl语言和R语言对数据进行提取、整理和分析,利用加权基因共表达网络(WGCNA)获取miRNA的共表达基因,并对筛选得到的差异表达miRNA进行Kaplan-Meier生存分析,筛选出对总生存时间存在影响的miRNA。通过与WGCNA筛选得到的共表达基因和miRNA靶基因预测数据库miRPathDB结合探寻其潜在靶基因,并通过metascape网站进行功能预测。结果通过TCGA共下载到6例正常、126例HCC癌组织的mRNA表达量数据集和6例正常、166例HCC癌组织的miRNA表达量数据集,通过生物信息学分析筛选出hsa-mir-139-5p差异表达具有显著意义,且对HCC总生存期有显著影响,通过预测其靶基因,发现其与脂质代谢、碳代谢等代谢通路相关。结论hsamir-139-5p可作为潜在的HCC治疗靶点,但需要后续实验验证。利用生物信息学手段筛选生物标志物或治疗靶标,是一种高效而经济的研究方式。     

Depressive-and anxiety-like behaviors involve an oxidative damage in the brain of stressed mice: protective effects of phosphodiesterase 2 inhibitor

Cyclic GMP-PKG signaling plays a crucial role in neuropsychiatric disorders such as depression/anxiety that is often characterized with oxidative stress and neuronal cell apoptosis.Phosphodiesterase 2(PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala,which may be important in treatment of depression and anxiety through regulation of oxidative stress and apoptosis.To address the possible effects of PDE2 inhibitor on depressive-and anxiety-like behaviors and on neurons of hippocampus and amygdala,different doses of Bay 60-7550(1 and 3 mg·kg-1,ip) were administered in chronically stressed mice.The data suggested that higher dose of Bay 60-7550 reversed chronic stress-induced depressive-and anxiety-like behaviors,which may be due to Bay 60-7550′s ability to alleviate oxidative stress and to reverse the adverse effect of stress on cGMP/PKG signaling,as assessed by Cu/Zn superoxide dismutase(SOD) levels,an enzyme involved in superoxide detoxfication,and phosphorylation of VASPser239,an indicator of PKG signaling in the hippocampus and amygdala.Interestingly,Bay 60-7550 regulates the SOD expression differentially in hippocampus and amygdala,which were increased in the hippocampus while decreased in the amygdala.Furthermore,Bay 60-7550 was found to decrease the expression of apoptosis related proteins in these two brain regions,such as Bax and caspase 3,which were induced by chronic stress.However,the expression of B cell lymphoma protein-2(Bcl-2) was increased after treatment with Bay 60-7550.These data strongly suggest that PDE2 produces antidepressant-and anxiolytic-like effects primarily through SOD-cGMP/PKG-antiapoptosis signaling,which indicates a potential candidate for treatment of neuropsychiatric disorders.