新型抗癫(癎)药物对脑缺血损伤的神经保护作用

目前很多体内体外的实验研究了新型抗癫(癎)药物的脑保护机制,本文将脑缺血和癫(癎)对脑的损伤机制以及新型抗癫(癎)药物的脑保护作用进行综述.     

广泛性焦虑障碍认知行为治疗的疗效评估中设置心理治疗安慰剂对照组或等待治疗对照组的比较:一项Meta分析(英文)

背景:安慰剂对精神障碍的治疗疗效一直颇为争议。在广泛性焦虑障碍治疗的随机对照研究中,心理治疗安慰剂对照或等待治疗对照是两种最常见的对照设置。但是,目前尚缺乏这两种不同的对照策略对临床疗效影响的系统评价。目标:通过广泛性焦虑障碍的随机对照研究数据,比较认知行为治疗与心理治疗安慰剂对照或与等待治疗对照时患者症状严重程度的变化。方法:在以下数据库中检索有关广泛性焦虑障碍的随机对照研究:PubM ed、PsycI nfo、EMBASE、Cochrane Library、中国知识资源总库、中国科技期刊数据库、万方数据检索系统、中国生物医学文献服务系统以及台湾电子期刊服务网数据库等。根据预先设定的纳入和排除标准筛选文献,根据研究的偏倚风险和证据质量水平对每项纳入的研究进行全面的方法学质量评价。采用RevM an 5.3软件进行Meta分析,使用R软件进行3组比较的网络meta分析。结果:共纳入12项研究,总计样本量531例。相较于任何一种对照的方法(安慰剂或等待治疗),认知行为治疗对广泛性焦虑障碍的疗效更好。用心理治疗安慰剂的方法能比等待治疗显著减轻症状。这些研究中有8项被为"高偏倚风险",研究的总体证据水平处于"中等",表明将来的研究可能会改变这一Meta分析的总体结果。结论:总体而言,广泛性焦虑障碍治疗的随机对照研究的研究质量中等。虽然这些研究表明认知行为治疗具有优势,但迄今为止这一结果还不稳健。在这些研究中,心理治疗安慰剂对照组的治疗效果不可忽略。在随机对照研究中,无论是研究设计时还是解释有关心理治疗干预效应的结果时都应充分考虑安慰剂效应。     

认知行为治疗和症状特异性药物治疗伴焦虑和抑郁的喉切除术后咽喉癌患者的回顾性比较(英文)

背景:喉切除术是一种常见的治疗喉癌损伤性手术作,可导致巨大的压力,但如何能减轻手术带来的心理影响知道甚少。目标:比较认知行为治疗(CBT)与药物治疗对喉切除术后咽喉癌患者焦虑和抑郁症状的治疗效果。方法:回顾湖州市第三人民医院2009年3月至2013年5月心理门诊中喉切除术后患有抑郁症或焦虑症患者的病历,确定63例患者曾接受过8周一对一的CBT治疗(其中无法说话的患者以书面形式作出回应),以及56例患者曾接受过8周的盐酸丁螺环酮治疗(n=11)、舍曲林治疗(n=9)或两种药物联合治疗(n=36)。治疗的选择(CBT或药物)是根据病人的陈述偏好而定的。采用焦虑自评量表(SAS)和抑郁自评量表(SDS)分别评估治疗前后的焦虑和抑郁症状。结果:治疗8周后,两组的SAS平均分和SDS平均分都明显下降,(根据焦虑自评量表和抑郁自评量表评分标准)伴有有焦虑或者抑郁症状患者的百分比也显著下降了。但是,两种治疗方法之间没有显著差异。药物治疗组32%的参患者在治疗过程出现一个或多个不良反应,但这些都没有严重到需要停药治疗。讨论:CBT是一种有效的、短期的治疗手段,可用于减少一个人被诊断患有癌症或接受癌症治疗后往往产生的焦虑和抑郁症状。众多证据表明,这些心理症状的治疗可以提高癌症患者的生活质量和减短疾病的病程,所以肿瘤学家和其他临床医生需要定期筛查癌症患者和其他危及生命的慢性病患者的抑郁和焦虑症状,如果存在的话,就需要积极对这些症状进行治疗。这项研究表明,CBT对于即使无法说话的癌症患者来说也是有效的。     

中国抗精神病药物治疗精神分裂症患者P300潜伏期和波幅变化的Meta分析(英文)

背景事件相关电位研究表明,精神分裂症患者的认知功能损害与P300的潜伏期和波幅有关,但尚不清楚这些认知功能的改变是否会随着药物治疗而改变。目的汇集中国的随访研究,确定抗精神病药物治疗与P300成分改变的关系。方法手工和电子检索1982年1月至2011年12月在中国进行的、以中文或英文发表的文献,内容为抗精神病药物治疗前后精神分裂症患者P300的潜伏期和波幅变化。2位评定者对12项符合Meta分析纳入标准的研究独立进行分析。12项研究中有17个样本的P300波幅峰值具有同质性,因而采用固定效应模型计算汇集的标准化效应值(pooledstandardized effect size,PSES);但P300潜伏期数值具有异质性,因而采用随机效应模型计算PSES。采用Egger’s和Begg’s检验及倒漏斗图分析发表性偏倚。结果汇集样本的611例受试者中,治疗前后完成P300潜伏期和波幅测试的502例(82.2%)纳入Meta 分析。发现抗精神病药物治疗与P300波幅微小但显著的增加有关(PSES=0.39, 95% CI [0.26, 0.51], z=6.14, p<0.001)及P300潜伏期微小但显著的减少有关(PSES= -0.29, 95% CI [-0.51, -0.07]; z=2.58; p=0.010)。无显著的发表偏移。结论既往西方的Meta分析主要是基于横断面研究,与此不同,中国的这一精神分裂症患者治疗随访研究的Meta分析发现P300波幅和潜伏期均随药物治疗而改变。提示P300成分,特别是P300波幅,可能是精神分裂症患者药物治疗期间监测认知功能变化的有价值的生物学标记。     

颞叶癫(癎)海马神经元凋亡机制的研究进展

颞叶癫(癎)的海马病理变化分子机制一直是神经学科研究的重点.在发现海马致(癎)灶中存在天冬氨酸特异性半胱氨酸蛋白酶3(caspases-3)后,学者们推测凋亡机制可能对颞叶癫(癎)海马病理的形成具有一定作用.近年来,许多学者建立了相应的实验模型或活体标本,以凋亡基础理论为依据,从不同角度对颞叶癫(癎)中海马神经元损伤的凋亡机制进行研究,相继发现了凋亡级联效应途径中其他分子的显著表达,包括死亡受体、凋亡效应酶、凋亡调节蛋白等,甚至在基因水平找到了凋亡存在的证据,同时也引发了抗凋亡的治疗研究,为颞叶癫(癎)海马神经元损伤分子机制的进一步研究及颞叶癫(癎)的药物治疗研究提供了理论基础.本文对此进行综述.     

Social fear conditioning: a novel and specific animal model to study social anxiety disorder

Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1?s, 0.7?mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.     

Auditory fear conditioning and conditioned stress raise NO(3) level in the Amygdala

BACKGROUND: The conditioned fear response is considered to be acquired by experimental animals when tone information is combined with that of an electrical foot shock (unconditioned stimulus) in the amygdala. Nitric oxide biosynthesized in the brain is reportedly involved in several kinds of learning. METHODS: In this study, we continuously monitored the NO(3)(-) level, as a marker of nitric oxide production, in the amygdala starting before the application of tone and electrical foot shock stimuli together (conditioned group) or the tone stimulus alone (control group) on day 1, until after the tone information was given (both groups) on day 2, using the in vivo microdialysis method. RESULTS: The NO(3)(-) level of the conditioned group was increased on both day 1 and day 2, while that of the control group was not elevated on either day. Freezing behavior was observed in the conditioned but not the control rats. CONCLUSIONS: Although the sources of NO(3)(-) remain uncertain, these results suggest that nitric oxide is associated with auditory fear conditioning and the response to a conditioned stimulus.     

A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear

The pathomechanisms of posttraumatic stress disorder (PTSD) are still unknown, but both fear conditioning and stress sensitisation are supposed to play a crucial role. Hence, valid animal models that model both associative and non-associative components of fear will facilitate elucidation of the biological substrates of the illness, and to develop novel and specific approaches for its prevention and therapy. Here we applied a single electric footshock to C57BL/6N (B6N) and C57BL/6JOla (B6JOla) mice and recorded the conditioned response to contextual trauma reminders (associative fear), the sensitised reaction to a neutral tone in a novel environment (non-associative fear, hyperarousal), social interaction and various emotional behaviours using Modified Holeboard, Test for Novelty-Induced Suppression of Feeding and Forced Swimming Test, after different incubation times (1, 14, 28 days). Freezing generally increased as a function of shock intensity. In B6N mice, sensitised fear was maximal 28 days after trauma and was accompanied by signs of emotional blunting and social withdrawal. B6JOla mice, in contrast, were less susceptible to develop PTSD-like symptoms. The phenotype of B6N exhibited high behavioural variance, allowing distinction between vulnerable and resilient individuals. Only in vulnerable B6N mice, chronic fluoxetine treatment - initiated after an incubation period of 28 days - ameliorated sensitised fear. This new mouse model fulfils common criteria for face and predictive validity and can be used to investigate the biological correlates of individual fear susceptibility, as well as the impact and interrelationship of associative and non-associative fear components in the development and maintenance of PTSD.     

Behavioral techniques for attenuating the expression of fear associations in an animal model of anxiety

Background and objectives

Recent data indicate that extinguished fear often returns when the testing conditions differ from those of treatment. Several manipulations including extensive extinction training, extinction in multiple contexts, and spacing the extinction trials and sessions reduce the return of fear. Moreover, extensive extinction and extinction in multiple contexts summate in reducing return of fear, and the spacing of the extinction trials and the spacing of extinction sessions summate in reducing return of fear. Here we evaluated whether these techniques also attenuate the context specificity of latent inhibition, and whether they summate to further decrease fear responding at test.

Methods

In two experiments, with rats as subjects in a lick suppression preparation, we assessed the effects of massive CS preexposure, CS preexposure in multiple contexts, and of spacing the CS-preexposure trials and sessions, in reducing the context specificity of latent inhibition.

Results

Fear responding was attenuated by all four manipulations. Moreover, extensive CS preexposure in multiple contexts, and conjoint spacing of the CS-preexposure trials and sessions, were more effective in reducing the context specificity of latent inhibition than each manipulation alone.

Limitations

Our experimental designs evaluated degrees of context specificity of latent inhibition but omitted groups in which latent inhibition was assessed without a context shift away from the context of latent inhibition treatment. This precluded us from drawing conclusions concerning absolute (as opposed to relative) levels of recovery from latent inhibition.

Conclusions

Techniques effective in decreasing the return of conditioned fear following extinction are also effective in decreasing the context specificity of latent inhibition in an animal model of anxiety. Fear and anxiety disorders might be prevented in anxious human participants with the same techniques used here, but that is still an empirical question.     

Depression and anxiety: from clinic to pharmacological treatment

Either as a symptom or as a trait of an axis I disorder, anxiety is frequently associated with depressive episodes. Its treatment depends mainly of the syndrome in which it is included. While the selective serotonin reuptake inhibitors seem to be indicated in depression with comorbid anxiety disorders and in anxious depression, in agitated depression may be preferable to indicate mood stabilizers or sedative antipsychotics. Benzodiazepines may be useful at the beginning of the treatment of these special forms of depression, but it is advisable to tapper them off once the affective and/or the anxiety disorders improve.     

Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder

Fear is an adaptive response that initiates defensive behavior to protect animals and humans from danger. However, anxiety disorders, such as Posttraumatic Stress Disorder (PTSD), can occur when fear is inappropriately regulated. Fear conditioning can be used to study aspects of PTSD, and we have developed a model in which pre-exposure to a stressor of repeated footshock enhances conditional fear responding to a single context-shock pairing. The experiments in this chapter address interpretations of this effect including generalization and summation or fear, inflation, and altered pain sensitivity. The results of these experiments lead to the conclusion that pre-exposure to shock sensitizes conditional fear responding to similar less intense stressors. This sensitization effect resists exposure therapy (extinction) and amnestic (NMDA antagonist) treatment. The pattern predicts why in PTSD patients, mild stressors cause reactions more appropriate for the original traumatic stressor and why new fears are so readily formed in these patients. This model can facilitate the study of neurobiological mechanisms underlying sensitization of responses observed in PTSD.     

Involvement of dopamine D(1) and D(2) receptors in the ethanol-associated place preference in rats exposed to conditioned fear stress.

The present study was designed to investigate: (1) the involvement of dopamine D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D(1) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D(1) and D(2) receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D(1) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu- and delta-opioid receptors, whereas D(2) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu-opioid receptors, but not in that modulated by the activation of delta-opioid receptors.     

Effects of the benzodiazepine antagonist flumazenil on conditioned fear stress in rats

1. The authors investigated the effect of the benzodiazepine receptor antagonist flumazenil on freezing behavior induced by conditioned fear stress and used a time-sampling procedure. 2. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. 3. Subcutaneous administration of flumazenil (10 mg/kg) 30 min before conditioned fear stress reduced conditioned freezing, while flumazenil (1-10 mg/kg) 30 min before footshock did not. This indicates that flumazenil reduced the expression of conditioned fear, suggesting an anxiolytic effect of flumazenil. 4. This effect may be attributable to antagonism by flumazenil to endogenous inverse agonist-like ligands for benzodiazepine receptors. It is suggested that endogenous inverse agonist-like ligands for benzodiazepine receptors are involved in the expression of conditioned fear stress.