创伤后应激障碍大鼠海马组织5-HT1受体mRNA的表达

目的探讨创伤后应激障碍(Posttraumatic Stress Disorder,PTSD)大鼠海马组织中5-羟色胺受体1mRNA的表达。方法随机将雄性wistar大鼠分为对照组和PTSD组,采用SPS(single-prolonged stress)方法刺激大鼠建立PTSD大鼠模型,Morris水迷宫实验检测大鼠记忆功能,化学发光法检测大鼠血清皮质醇浓度。SPS刺激后1d、4d、7d、14d分离海马组织,RT-PCR方法检测5-羟色胺受体1的变化。结果 (1)对照组水迷宫实验逃避潜伏期为(5.632±1.065)s,模型组为(20.762±3.236)s(t=9.932,P0.01);(2)对照组血清皮质醇浓度为(1.25±0.12)μg/dl,模型组为(0.58±0.09)μg/dl(t=7.340,P0.01);(3)SPS刺激后1d、4d、7d、14d海马5-HT1A受体mRNA表达相对水平分别为0.846±0.067、0.510±0.052、1.007±0.137、1.109±0.106,与对照组相1.223±0.152比较,1d、4d、7d表达低于对照组(P0.05);5-羟色胺1受体其他亚型未见表达。结论 PTSD大鼠海马中5-HT1A受体mRNA表达降低。     

创伤后应激障碍大鼠海马中脑源性生长因子的表达变化

目的研究创伤后应激障碍(PTSD)大鼠血浆、海马CA_1区和齿状回神经元内脑源性生长因子(BDNF)的变化。方法用单一连续刺激(SPS)方法刺激大鼠产生PTSD模型,另进行强迫游泳(FS)刺激作为对照,ELISA检测不同时间(正常、刺激后2 h、12 h、1 d、7 d以及7 d后再次给予强迫游泳后2 h)大鼠血浆BDNF;取SPS后2 h、7 d、SPS+再次游泳后2 h和FS+再次游泳后2 h鼠脑组织,正常脑组织为对照,免疫组织化学技术观察大鼠海马神经元内BDNF的表达,以及采用荧光实时定量PCR法检测大鼠海马神经元内的BDNF-mRNA相对表达。结果大鼠经SPS刺激后2 h时血浆BDNF明显高于正常,7 d时与正常大鼠无明显差异,SPS+再游泳-2 h时明显高于各时间段及FS+再游泳后2 h;大鼠海马CA1区、齿状回内BDNF的表达以及海马内BDNF-mRNA相对表达也出现相似的改变。结论 PTSD大鼠血浆中BDNF浓度变化与海马内BDNF表达相关,BDNF的改变影响PTSD大鼠对创伤刺激的恐惧记忆形成、巩固和再摄取。     

次声对大鼠海马5-HT、5-HTR、RyR表达及恢复的研究

目的研究大鼠海马5-羟色胺(5-HT)、5-羟色胺受体(5-HTR)、兰尼定受体(RyR)表达在8 Hz、130 dB的次声作用后1周和2周时的恢复情况. 方法大鼠暴露于8 Hz、130 dB次声1、7、14、21、28、35、42 d后置安静环境观察1周或2周,取脑组织并进行免疫组织化学染色,光学显微镜下观察海马5-HT、5-HTR、RyR表达. 结果次声作用组大鼠脑组织海马5-HT、5-HTR、RyR表达均较对照组减少,最低值分别出现于21 d、28 d和42 d(P<0.01).次声停止作用后,5-HT、5-HTR、RyR表达均逐渐回升,且随时间延长大部分恢复到正常对照水平.结论 8 Hz、 130 dB次声可引起大鼠海马5-HT、5-HTR、RyR表达减少,其变化规律与观察指标有关;次声引起的5-HT、5-HTR、RyR表达减少在停止次声作用后可逐渐恢复正常.     

创伤后应激障碍的睡眠障碍

尽管睡眠障碍在精神疾病中非常常见，但他常常被当作精神疾病的二级症状，认为对其主要精神疾病的治疗才是缓解睡眠苦恼的最可行办法。事实上，比如创伤后应激障碍(PTSD)的噩梦并不随总症状评分的下降而减少，有时可持续很长时间，而采用针对睡眠紊乱的治疗方案后，超过50％患者的创伤后应激症状可得到有效缓解。现论述PTSD对睡眠的影响，并讨论睡眠紊乱的治疗问题。     

成人创伤后应激障碍海马体积研究的Meta分析

目的 综合评价成人创伤后应激障碍(Posttraumatic stress disorder,PTSD)的左、右侧海马体积.方法 利用Meta分析方法对国内外公开发表的关于成人PTSD左、右侧海马体积的研究文献进行综合定量分析.结果 共收集到符合纳入标准的文献23篇,累计病例共337例,累计对照共389名.PTSD组与健康对照组左侧海马体积分析显示,总体效应检验有统计学意义(Z=4.77,P<0.01),95%CI横线位于无效竖线左侧.提示PTSD的左侧海马体积减小;PTSD组与健康对照组右侧海马体积比较分析显示,总体效应检验有统计学意义(Z=5.01,P<0.01),95%CI横线位于无效竖线左侧,提示PTSD的右侧海马体积减小.漏斗图分布呈倒漏斗形,近似对称,Begg检验证实发表无偏倚.结论 成人PTSD患者左、右侧海马体积均减小.     

重症监护病房患者配偶创伤后应激障碍海马体积的研究

目的:探索重症监护病房(ICU)患者配偶中患创伤后应激障碍(PTSD)者双侧海马体积变化。方法:采用3.0 T磁共振检查(MRI)对20例ICU患者之配偶中患有PTSD者(PTSD组)及20例未患有PTSD者(对照组)进行全脑3D T1扫描;使用FreeSurfer获取并分析双侧海马体积变化,同时分析PTSD组双侧海马体积与PTSD诊断量表(CAPS)得分的相关性。结果:与对照组比较,PTSD组的双侧海马体积均显著缩小,差异具有统计学意义(P均0.01),但左侧海马体积减小比例大于右侧(左侧15%,右侧11%)。同时PTSD组的左右侧海马均与CAPS得分呈负相关(P均0.05)。结论:ICU患者配偶中患有PTSD者其海马体积存在缩小并存在偏侧性,需要给予及时有效的关心和干预。     

创伤后应激障碍的心理治疗

心理治疗被认为是创伤后应激障碍(PTSD)的首选治疗方案.根据目前的理论解释和文献研究,认知行为治疗技术如暴露治疗、焦虑管理训练、认知治疗等对PTSD比较有效.眼动脱敏和再加工 治疗方法可能对PTSD有效,但需要进一步的研究支持.本综述从理论解释、具体方法、效果研究和治疗原则等方面介绍PTSD的心理治疗技术.     

慢性应激模型大鼠脑内5-HT1A受体表达分析

目的 探讨慢性不可预见性轻度应激(CUMS)模型大鼠各脑区(海马、中缝核、前额叶及纹状体)5-HT1A受体表达及与旷场行为变化的关系;西酞普兰对5-HT1A受体表达的影响.方法 将24只雄性SD大鼠随机分为3组(n=8):A组为对照组;B组为CUMS应激组;C组为CUMS应激+西酞普兰用药组(每天腹腔注射西酞普兰水溶液2 ml,10mg/kg).实验为期6周,通过旷场试验评价大鼠行为,6周后处死大鼠获取脑组织,采用Real-Time PCR检测各脑区5-HT1A mRNA表达水平,并分析其与矿场行为的相关性.结果 B组海马5-HT1A mRNA表达较A组有增高趋势(P=0.05),其余各脑区5-HT1A mRNA表达均差异无统计学意义(P＞0.05).海马5-HT1AmRNA表达大鼠移动次数、转身次数呈正相关,与总不动时间呈负相关;中缝核、纹状体5-HT1A mR-NA表达与中心移动距离呈正相关,纹状体5-HT1A mRNA表达与中心停留时间呈正相关(P均＜0.05).结论 慢性应激可能会引起海马5-HT1A受体表达增高;抗抑郁剂西酞普兰对5-HT1A受体表达无影响.5-HT1A mRNA表达与旷场行为变化有相关性.     

创伤后应激障碍

本文介绍创伤后应激障碍及其有关的几个问题。     

创伤后应激障碍的神经生物学机制

美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)关于创伤后应激障碍(PTSD)的定义中所述及的症状是因为中枢神经系统对应激信息的记忆过程出现了障碍，使条件化的恐惧反应难于抑制或过分抑制所致。目前关于其产生机制包括以下方面：     

Reduction in 5-HT1A receptor density, 5-HT1A mRNA expression, and functional correlates for 5-HT1A receptors in genetically defined aggressive rats

The present experiments tested the hypothesis that one of the critical mechanisms underlying genetically defined aggressiveness involves brain serotonin 5-HT1A receptors. 5-HT1A receptor density, the receptor mRNA expression in brain structures, and functional correlates for 5-HT1A receptors identified as 8-OH-DPAT-induced hypothermia and lower lip retraction (LLR) were studied in Norway rats bred for 59 generations for the lack of aggressiveness and for high affective aggressiveness with respect to man. Considerable differences between the highly aggressive and the nonaggressive rats were shown in all three traits. A significant decrease in B(max) of specific receptor binding of [3H]8-OH-DPAT in the frontal cortex, hypothalamus, and amygdala and a reduction in 5-HT1A receptor mRNA expression in the midbrain of aggressive rats were found. 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and did not affect significantly the body temperature in aggressive rats. Similar differences were revealed in 8-OH-DPAT-induced LLR: LLR was expressed much more in nonaggressive than in aggressive animals. Additionally, 8-OH-DPAT (0.5 mg/kg i.p.) treatment significantly attenuated the aggressive response to man. The results demonstrated an association of aggressiveness with reduced 5-HT1A receptor expression and function, thereby providing support for the view favoring the idea that brain HT1A receptor contributes to the genetically defined individual differences in aggressiveness.     

5-HT1B mRNA expression after chronic social stress

Chronic stress contributes to vulnerability for depression and drug addiction. The function of the serotonergic system has been found to be modified by chronic stress and these changes may play an important role in stress-related relapses to drug craving. The 5-HT_1B receptor is expressed in nucleus accumbens (NAc) projection neurons and modulates drug reward mechanisms and there is evidence suggesting that stress alters the regulation and function of these receptors. To examine the role of these receptors in integrating the effects of stress on reward mechanisms, we examined whether chronic or acute social defeat stress (SDS) regulates 5-HT_1B mRNA in dorsal and ventral striatum, regions that are critical for integrating the effects of environmental stressors on reward motivated behavior. In addition, 5-HT_1B mRNA regulation in response to another acute stressor, inescapable tailshock, was measured. Our results indicate that intermittent and daily SDS procedures attenuated body weight gain, induced adrenal hypertrophy, and reduced the preference for saccharin, a sweet solution preferred by normal rats. There was a trend for daily, but not intermittent SDS to increase 5-HT_1B receptor mRNA levels in nucleus accumbens. Therefore, in the next experiment, we examined daily SDS in greater detail and found that it increased 5-HT_1B receptor mRNA expression in rostral nucleus accumbens shell, an area especially associated with reward functions. Neither acute SDS, nor acute tailshock stress had a significant impact on 5-HT_1B mRNA expression in the striatum. Since increased 5-HT_1B receptor expression in nucleus accumbens shell neurons can facilitate cocaine and alcohol reward mechanisms, this adaptation in endogenous 5-HT_1B mRNA may be involved in the SDS-associated increase in vulnerability for developing addiction.     

Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain

We evaluated the effects of adrenalectomy (ADX) and replacement with glucocorticoid receptor agonists on serotonin (5-HT) 5-HT_1A and 5-HT₂ receptor binding in rat brain. 5-HT_1A receptor binding was increased in the CA2–CA4 and the dentate gyrus of the hippocampus 1 week after ADX. This effect was prevented by the systemic administration of aldosterone (10 μg/μl/h) but not by RU28362 (10 μg/μl/h). No significant effect was observed on 5-HT₂ receptor binding in rat cortex. The expression of 5-HT transporter mRNA was unchanged in the raphe nucleus as measured by in situ hybridization.     

大鼠脊髓内5-HT2C,5-HT3,5-HT6和5-HT7受体亚型mRNAs的表达

目的:观察5-HT2C,5-HT3,5-HT6和5-HT7受体亚型mRNAs在大鼠脊髓不同节段的表达.方法:反转录PCR方法.结果:5-HT2C受体亚型mRNA在颈、胸、腰、骶段脊髓的背角(DH)和前角(VH)均有较强的表达;5-HT3受体mRNA在各节段脊髓DH的表达水平较高,而在VH则较低;与5-HT3受体亚型相反,5-HT6受体亚型mR-NA在脊髓VH的表达水平高于DH;5-HT7受体mRNA在脊髓的表达则与5-HT3受体相似,在各节段的DH均有较高水平的表达.不同的受体亚型在脊髓同一节段以及同一受体亚型在不同脊髓节段的表达水平存在差异.结论:本研究结果表明,上述四种5-HT受体亚型在脊髓具有不同的表达特点,提示它们在脊髓水平可能发挥着不同的生理作用,并为深入探讨5-HT受体参与伤害性感受和运动的调节机制提供了依据.     

5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study.

In this study, we have identified and characterized 5-HT₃-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT₃ binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT₃ receptor agonist 3-methylserotonin (2-Me-5HT), similar to the action of 5-HT), produced a current-dependent (10–80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT₃ receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10–20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT₃ antagonists, with a rank order of effectiveness as follows: JCS 205930=(±)-zacopride>granisetron=ondansetron= LY 278584 >MDL72222. Furthermore, the intravenous administration of(±)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT₃ receptors antagonists, other receptor antagonists such as metergoline (5-HT_1A,1B,1C,2), (±)-pindolol (5-HT_1A,1B,β), SCH 23390 (5-HT_1C,2, D1), 1-sulpiride (D2) or SR 95103 (GABA_A) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT₃-like receptors.     

Serotonergic signalling between thyroid cells: protein kinase C and 5-HT2 receptors in the secretion and action of serotonin.

Parafollicular (PF) cells of the thyroid gland are neural crest derivatives, which costore the neurotransmitter, 5-hydroxytryptamine (5-HT) with calcitonin. PF cells are located adjacent to follicular (F) cells within the basement membrane of thyroid follicles. It has been proposed that 5-HT serves an intercellular signalling function in the thyroid and that F cells are its target. This proposal was tested by using cell lines derived from PF (medullary thyroid carcinoma [MTC]) and F (FRTL-5) cells to study the mechanisms that mediate the secretion and action of 5-HT. Secretion of 5-HT by MTC cells was evoked by thyroid stimulating hormone, thyrotropin (TSH), elevated extracellular calcium (increases [Ca2+]e), or by agents that increase intracellular cAMP (increases [cAMP]i). When protein kinase C (PKC) was down-regulated by prolonged treatment of MTC cells with phorbol 12-myristate 13-acetate (PMA), or PKC was inhibited by staurosporin, the TSH- or PMA-evoked secretion of 5-HT was blocked; however, interference with PKC function did not affect 5-HT secretion evoked by increases [Ca2+]e or increases [cAMP]i. In the putative targets, FRTL-5 cells, 5-HT increased the turnover of phosphoinositides (PI), cytosolic calcium (increases [Ca2+]i), increases [cAMP]i, and biphasically modified the effect of TSH on cAMP. All of these 5-HT effects were inhibited by 5-HT2 receptor antagonists (spiperone and ketanserin) and by pertussis toxin (PTx), suggesting that the actions of 5-HT are mediated by 5-HT2 receptors, which are coupled to a G protein. This suggestion was supported by the following additional observations: FRTL-5 membranes bound the 5-HT2 agonist, [125I]2,5-dimethoxy-4-iodophenylisopropylamine ([125I]-DOI), and anti-idiotypic antibodies, which recognize 5-HT2 receptors. [125I]-DOI binding was inhibited by guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma-S) and the antibodies were displaced by spiperone. Data are consistent with the hypothesis that 5-HT serves as a PF to F cell messenger.     

Involvement of 5-HT1B receptors in the anticonflict effect of m-CPP in rats

Summary The anticonflict activity of m-CPP, a non-selective agonist of 5-HT receptors, was studied in the drinking conflict test in rats. m-CPP administered in doses of 0.125–0. 5 mg/kg increased the number of punished licks, the maximum effect having been observed after a dose of 0.25 mg/kg. The anticonflict effect of m-CPP (0.25 mg/kg) was antagonized by the non-selective 5-HT antagonist metergoline (1–4 mg/kg) and by the -adrenoceptor blocker SDZ 21009 (2 and 4 mg/kg) with affinity for 5-HT_1A and 5-HT_1B receptors. On the other hand, the 5-HT_1A receptor antagonist NAN-190 (0.5 and 1 mg/kg), the 5-HT₂ receptor antagonist ritanserin (0.25 and 0.5 mg/kg), and the -blockers betaxolol (8 mg/kg) and ICI 118,551 (8 mg/kg) with no affinity for 5-HT receptors did not affect the effect of m-CPP. The effect of m-CPP was not modified, either, in animals with the 5-HT lesion produced by p-chloroamphetamine.These results suggest that the anticonflict effect of m-CPP described above results from stimulation of 5-HT_1B receptors — most probably these which are located postsynaptically.     

The role of 5-HT(1A) receptors in control of lower urinary tract function in cats

In the present study, the role of 5-HT(1A) receptors in control of lower urinary tract function in cats was examined using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) as agonists and WAY100635 and LY206130 as antagonists. Bladder function was assessed using cystometric infusion of saline or 0.5% acetic acid to produce bladder irritation. External urethral sphincter (EUS) function was assessed using electromyographic (EMG) recordings of activity recorded during cystometry or by recording electrically evoked pudendal reflexes. Both 5-HT(1A) receptor agonists caused dose-dependent decreases in bladder activity and increases in EUS EMG activity under conditions of acetic acid infusion. 5-HT(1A) receptor antagonists reversed both the bladder-inhibitory and sphincter-facilitatory effects. Thus, 5-HT(1A) receptor activation can have opposite effects on nociceptive afferent processing depending upon the efferent response being measured. During saline infusion of the bladder, 8-OH-DPAT produced moderate inhibition of bladder activity and had no significant effect on sphincter electromyographic (EMG) activity. 8-OH-DPAT either had no effect, or inhibited, low-threshold electrically evoked pudendal reflexes. These findings indicate that 5-HT(1A) receptor stimulation is inhibitory to bladder function in cats, especially under conditions where the bladder is hyperactive due to irritation. Furthermore, these bladder-inhibitory effects are the exact opposite of the bladder-excitatory effects of 8-OH-DPAT reported in rats. 5-HT(1A) receptor stimulation increases EUS motoneuron activity when driven by nociceptive bladder afferent inputs but not when driven by non-nociceptive afferent inputs. In summary, 5-HT(1A) receptor agonists facilitate a nociceptor-driven spinal reflex (sphincter activity) but inhibit a nociceptor-driven supraspinal reflex (micturition). This pattern of activity would facilitate urine storage and may be important under 'fight-or-flight' conditions when serotonergic activity is high.