Behavioral profile of L‐655,708, a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit,in social encounters between male mice

GABA‐A receptor is a transmembrane hetero‐oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. It is well‐known that the GABAergic system is involved in the modulation of aggression. However, the role of α5/GABA‐A receptors has not been explored. In this study, we examined the effect of L‐655,708 (0.625‐5 mg/kg), a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to an anosmic “standard opponent” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. L‐655,708 (5 mg/kg) exhibited an ethopharmacological profile characterized by a marked reduction of the time spent in offensive behavior (threat and attack) without affecting immobility, accompanied by a significant increase of avoidance/flee and nonsocial exploration behaviors, suggesting that the antiaggressive effect of the drug is unselective. Overall, this behavioral profile might indicate the existence of an anxiogenic‐like activity of L‐655,708 in mice. Aggr. Behav. 30:319–325, 2004. © 2004 Wiley‐Liss, Inc.     

Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms

Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.     

应激性抑郁样行为发生中海马5-羟色胺1A受体的作用及其对NMDA受体和AMPA受体的调节

为探讨慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A, 5-HT1AR)表达与作用, 及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid, AMPA)受体的影响。通过建立CUMS动物模型, 给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂, 测量大鼠体重变化率, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平。结果显示, 与对照组相比, CUMS组大鼠表现出抑郁样行为, 海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低, NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加; 正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635, 动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同; 注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变。以上结果表明, CUMS诱发抑郁样行为与海马5-HT1AR表达下降, AMPAR表达量及磷酸化水平降低, NMDAR表达量及磷酸化水平升高有关。5-HT通过5-HT1AR产生抗抑郁作用。5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平, 提高AMPAR表达量及磷酸化水平密切相关。     

Appetitive memory reconsolidation depends upon NMDA receptor-mediated neurotransmission

Memory persistence is a dynamic process involving the reconsolidation of memories after their reactivation. Reconsolidation impairments have been demonstrated for many types of memories in rats, and signaling at N-methyl-d-aspartate (NMDA) receptors appears often to be a critical pharmacological mechanism. Here we investigated the reconsolidation of appetitive pavlovian memories reinforced by natural rewards. In male Lister Hooded rats, systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801, 0.1 mg/kg i.p.) either before or immediately following a brief memory reactivation session abolished the subsequent acquisition of a new instrumental response with sucrose conditioned reinforcement. However, only when injected prior to memory reactivation was MK-801 effective in disrupting the maintenance of a previously-acquired instrumental response with conditioned reinforcement. These results demonstrate that NMDA receptor-mediated signaling is required for appetitive pavlovian memory reconsolidation.     

ICU患者低磷血症临床观察与思考

回顾性分析41例低磷血症患者血磷水平与同期血气分析、血浆白蛋白(ALB)、尿素氮(BUN)等因素间关系及治疗前后急性生理和慢性健康评分(APACHE)Ⅱ的变化.结果显示脓毒症组血磷降低程度最明显,该组APACHEⅡ评分及纠正低磷血症所需时间显著高于其他基础疾病组.治疗前重度低磷血症组患者血pH、BUN显著高于轻中度低磷血症组,而PaCO2及ALB则明显低于轻中度低磷血症组;治疗前重度低磷血症组与轻中度低磷血症组间APACHE Ⅱ评分有显著差异,而治疗后两组间差异消失.病因治疗辅以适当补磷治疗可有效纠正低磷血症.由此得出结论,脓毒症患者易继发低磷血症.危重症患者重度低磷血症的发生与机体内酸碱环境改变及感染、高分解代谢等因素有关.低磷血症程度与疾病严重程度有关,但尚不足以成为独立的预后指标.     

东莨菪碱对大鼠空间参考记忆和工作记忆的不同影响

观察东莨菪碱对空间参考记忆和空间工作记忆的编码、保持和提取过程的作用。应用Morris水迷宫实验测定大鼠的空间参考记忆和空间工作记忆,分别在训练的不同阶段腹腔注射东莨菪碱（1mg/kg）和相同容量的生理盐水,比较各东莨菪碱组和生理盐水组之间游泳潜伏期、路径长度、轨迹和游泳速度的差异。结果发现：与注射生理盐水相比,在训练前和探测实验前注射东莨菪碱的大鼠在探测实验中对目标象限不表现出空间偏爱,说明东莨菪碱干扰参考记忆的信息编码和提取过程;而在训练结束后注射东莨菪碱的大鼠探测实验的结果与生理盐水组相比没有显著差异,说明东莨菪碱对参考记忆的保持过程没有影响。在工作记忆实验中,无论第一次测试前、第一次测试后和第2次测试前注射东莨菪碱,均造成大鼠游泳潜伏期延长,说明东莨菪碱干扰工作记忆的编码、保持和提取过程。研究提示M受体在空间工作记忆和参考记忆中发挥不同作用     

肝细胞生长因子受体在胶质母细胞瘤术后放疗过程中的价值评价

为了探讨脑胶质母细胞瘤术后放疗对肝细胞生长因子受体表达规律的影响,对25例胶质母细胞瘤患者进行研究。结果显示肝细胞生长因子受体在复发前接受放疗与未接受放疗的患者中,复发后肝细胞生长因子受体表达及复发时间差异明显（P〈0．05）。因此放疗能对肝细胞生长因子受体在胶质母细胞瘤的表达产生影响,进而影响到其复发时间。     

对恶性肿瘤性别差异的再认识

恶性肿瘤性别差异表现在发病率、预后、治疗等多方面。生理结构、生活方式、工作、性格等流行病学因素是造成恶性肿瘤性别差异的外因,性激素及其受体研究在一定程度上解释了性别差异的本质,且为恶性肿瘤的内分泌治疗提供了理论依据。随着分子生物学技术发展,基因多态、分子突变等深入研究成果揭示更深层次的原因。     

d-Serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior

Male Sprague Dawley rats were allowed to self-administer cocaine (0.5 mg/kg) during 90 min sessions for a period of 15 days. On day 16, rats were either held abstinent in their home cage environment or experienced an extinction session in which the active lever had no programmed consequences. Facilitating N-methyl-d-aspartate (NMDA) receptor activity with the coagonist d-serine (100 mg/kg i.p.) before or following the extinction session significantly reduced the subsequent cocaine-primed reinstatement of drug-seeking behavior tested on day 17. d-Serine significantly reduced drug-primed reinstatement only when combined with extinction, and its effectiveness when administered following the training session suggested that an enhancement of consolidation of extinction learning had occurred. In contrast, d-serine treatment did not reduce sucrose-primed reinstatement, indicating that the beneficial effects of this adjunct pharmacotherapy with extinction training were specific to an addictive substance (cocaine) and did not generalize to a natural reward (sucrose).