Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA (‘Ecstasy’) to rats

An investigation has been made into the effect of 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) administration on the concentration of 5-hydroxytryptamine (5-HT), uptake of [³H]5-HT and [³H]paroxetine binding in rat cerebral cortex tissue. Four days after 2 injections of MDMA (20 mg/kg i.p., 6 hr apart) the concentrations of 5-HT and its metabolite 5-HIAA were reduced by 60%. The binding of [³H]paroxetine to the presynaptic 5-HT transporter was decreased and high affinity uptake of [³H]5-HT was reduced by a similar amount, indicating neurodegeneration of 5-HT terminals. Pretreatment with chlormethiazole (100 mg/kg i.p.), 10 min before each MDMA injection prevented the decrease in both [³H]parotextine binding and uptake of [³H]5-HT. The loss in 5-HT and 5-HIAA content was also attenuated. Pretreatment with dizocilpine (1 mg/kg i.p.) or haloperidol (2 mg/kg i.p.) also prevented the MDMA-induced loss of [³H]paroxetine binding and attenuated the loss of 5-HT and 5-HIAA content. All three compounds also decreased the degree of hyperthermia that follows MDMA administration, although previous studies suggest that the long term neurodegeneration is not associated with the acute hyperthermic response. These data support the findings of others that MDMA injection produces degeneration of 5-HT nerve terminals in the cortex, confirm that chlormethiazole, dizocilpine and haloperidol attenuate MDMA-induced neurotoxic loss of 5-HT and demonstrate for the first time that these compounds prevent the neurodegeneration of 5-HT nerve terminals that follows MDMA administration.     

Moclobemide and specific serotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders

This retrospective study was undertaken with the objective of determining how effective and safe moclobemide, a specific and reversible inhibitor of monoamine oxidase-A (RIMA), is when used in combination with specific serotonin re-uptake inhibitors (SSRIs), in a clinical setting. A thorough chart review was done of all patients with affective and anxiety disorders seen at our centre who received combination treatment with moclobemide and an SSRI. Combination moclobemide-SSRI treatment demonstrated good efficacy in treating treatment-resistant patients. The combination treatment was well tolerated with very few drug interactions. Dosages should be started low, titrated slowly and carefully, and patients should be monitored closely.     

HPLC-MS同时测定4种新型抗抑郁药物的血药浓度

目的:建立一种快速灵敏的同时测定血浆中氟西汀、西酞普兰,帕罗西汀及文拉法辛浓度的 HPLC-MS 方法,监测这4种药物的血药浓度,为临床用药提供依据。方法:以氟伏沙明作为内标,样品碱化后固相萃取,用 MACHEREY-NAGEL C_(18)反相色谱柱(4.6 mm×250 mm,5μm,Germany)进行分离,以乙腈-缓冲盐(30 mmol 醋酸铵和0.6‰甲酸)(65:35)为流动相,柱温40℃,流速0.85 mL·min~(-1)。采用质谱电喷雾电离源(ESI)将样品离子化,选择性离子监测(SIM)准分子离子峰。结果:氟西汀、西酞普兰、帕罗西汀,文拉法辛及内标氟伏沙明在9 min 内完全分离;各物质在5～1000 ng·mL~(-1)时线性关系良好,相关系数均大于0.9964;萃取回收率均大于73.2%;方法回收率均大于95.0%;最低检测浓度:氟西汀0.5 ng·mL~(-1)、西酞普兰0.3 ng·mL~(-1)、帕罗西汀0.3 ng·mL~(-1),文拉法辛0.1 ng·mL~(-1);日内日间变异系数均小于15%。结论:本方法简便快速,灵敏准确,可用于血药浓度的临床监护、中毒分析,药物动力学以及代谢机制的研究。     

抗焦虑药物对束缚应激大鼠作用的分子机制探索

目的：为了探讨抗焦虑药物治疗焦虑症状的分子作用机制。方法：建立大鼠束缚应激模型，观察抗焦虑药物帕罗西汀用药组大鼠的旷场行为和下丘脑c-fos的表达。结果：与正常对照组比较，应激大鼠在旷场中的穿行格数和直立次数明显增加，下丘脑室旁核c-fos表达显著增加，而帕罗西汀用药组能减少大鼠在旷场中的活动和下丘脑室旁核c-fos表达。结论：帕罗西汀对束缚应激大鼠脑保护作用可能与下调c-fos基因表达有关。     

Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Background:

Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.

Methods:

Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats.

Results:

Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin_1A receptors; paroxetine (10mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin_1A receptors.

Conclusions:

The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin_1A receptors in hippocampus.     

丁螺环酮与帕罗西汀联合治疗抑郁症的临床研究

目的探讨丁螺环酮与帕罗西汀联合治疗抑郁症的疗效。方法符合ICD-10或CCMD-3抑郁症诊断标准的门诊和住院病人79例，随机分成两组，分别用丁螺环酮联合帕罗西汀和单用帕罗西汀治疗6周，采用汉密尔顿抑郁量表（HAMD）、汉密尔顿焦虑量表（HAMA）评定疗效，用副反应量表（TESS）评定副反应。结果6周末联合组HAMD和HAMA评分低于单用组。在第2周末、第6周末联合组的HAMD和HAMA的平均减分率高于单用组。两组间的副反应情况相仿。结论丁螺环酮联合帕罗西汀治疗抑郁症的疗效优于单用帕罗西汀。     

黛力新联合帕罗西汀治疗脑卒中后抑郁的临床观察

目的 观察黛力新联合帕罗西汀治疗脑卒中后抑郁患者的临床疗效. 方法 按照随机数字表法将我院收治的90例脑卒中后抑郁患者随机分为观察组和对照组. 两组患者均行脑卒中常规治疗,观察组在常规治疗基础上联合应用黛力新和帕罗西汀,对照组在常规治疗基础上单纯应用黛力新,28d为1个疗程. 观察对比两组患者的临床疗效、汉密顿抑郁量表( HAMD)评分、日常生活能力量表( ADL)评分、抑郁自评量表SDS、神经功能缺失评分NIHSS等情况. 结果疗程结束后,观察组总有效率达93. 3%,对照组总有效率为75. 6%,两组比较差异有统计学意义( P＜0. 05 );且观察组患者治疗后7d、28d的HAMD评分、ADL、SDS评分优于对照组,NIHSS优于对照组,两组比较差异有统计学意义(P＜0. 05).结论 联合应用黛力新和帕罗西汀治疗PSD,可有效改善患者抑郁,促进神经功能恢复,提高认知能力,比单纯应用黛力新的疗效更为显著,值得临床推广应用.     

Mirtazapine versus paroxetine in panic disorder: an open study

Introduction

Open studies suggest that mirtazapine has efficacy in panic disorder treatment. We designed an open study that evaluates changes induced by mirtazapine compared with paroxetine in panic disorder.

Methodology

Patients 18–65 years old consecutively referred to a psychiatry liaison service with panic disorder (DSM-IV criteria) were offered either mirtazapine or paroxetine treatment.

Results

There were statistically significant reductions from baseline to week 3 and from week 3 to 8 for mirtazapine and paroxetine groups for: number of panic attacks, Beck Anxiety or Depression Inventory (BAI, BDI) Clinical Global Impresion (CGI) of panic disorder severity and CGI of panic disorder response (these variables were evaluated by the patient, the clinician or a blind evaluator). Responders at week 3 (BAI decrease of 50%) were 83% for the mirtazapine group and 84% for the paroxetine group. Responders at week 8 (number of panic attacks equal to 0) were 77% for the mirtazapine group and 73% for the paroxetine group Statistically significant differences between mirtazapine and paroxetine were found for number of panic attacks at weeks 3 and 8 and BAI at week 3, suggesting a faster response for mirtazapine. Responders at week 8 maintained a no recurrence figure of 95% at follow-up 6 months later. Panic disorder either with or without comorbid depression improved in both groups of treatment.

Discussion

Our study supports the hypothesis that mirtazapine has efficacy in the treatment of panic disorder either with or without comorbid depression.     

四逆散冻干粉改善大鼠睡眠作用机制研究

目的研究四逆散冻干粉改善大鼠睡眠作用机制。方法按照随机数表法将SD雄性大鼠随机分为5组:空白对照组、阴性对照组、阳性对照组、四逆散冻干粉组,混合物组,每组10只。阴性对照组的大鼠灌胃0. 9%Na Cl;阳性对照组的大鼠灌胃盐酸帕罗西汀溶液4. 2 mg·kg^-1;四逆散冻干粉组的大鼠灌胃四逆散冻干粉水煎液2. 41 g·kg^-1;混合物组灌胃混合物(辛弗林-芍药苷-柴胡皂苷C-甘草次酸=8. 5∶1. 0∶1. 5∶6. 5) 206 mg·kg^-1。每日灌胃1次,连续给药1周。用高效液相色谱(HPLC)法测定脑脊液移行成分。结果四逆散冻干粉在脑脊液中除戊巴比妥钠成分外,并无血中移行成分的进入;给予四逆散冻干粉后,脑脊液中成分峰面积约是空白脑脊液峰面积的12. 5倍;血清中四逆散的移行成分(辛弗林、芍药苷、柴胡皂苷C、甘草次酸)均可以使脑脊液中该内源性物质峰面积高于空白脑脊液峰面积,但不如四逆散整方作用;混和物组增高脑脊液中内源性物质峰面积是四逆散组的3. 2倍,该内源性物质是5-羟色胺。结论四逆散冻干粉是通过促进脑脊液中内源性物质5-羟色胺的分泌达到改善睡眠作用的。