胍丁胺对慢性应激大鼠海马神经元和星形胶质细胞的影响

目的在海马神经元和星形胶质细胞水平探讨胍丁胺抗抑郁作用机制。方法采用多种应激方式建立大鼠慢性应激抑郁模型,通过开场实验和蔗糖饮水实验观察模型组、阳性对照药氟西汀组(10 mg.kg-1,ig)和胍丁胺组(20 mg.kg-1,ig)大鼠的行为学变化;应用神经元标志物——微管相关蛋白2(microtubule-associated protein 2,MAP2)和星形胶质细胞标志物——胶质原纤维酸性蛋白(glial fibrillary acidicprotein,GFAP)免疫组织化学染色,观察各组大鼠海马神经元和星形胶质细胞形态改变。结果慢性应激模型组大鼠开场实验水平运动得分和垂直运动得分明显降低,蔗糖偏嗜度明显降低,氟西汀和胍丁胺可逆转此变化;免疫组化结果显示,慢性应激模型组MAP2和GFAP表达明显减弱,表现为海马神经元突起长度和数目以及星形胶质细胞的数量和突起数量明显降低,氟西汀和胍丁胺可改善此病理变化。结论海马神经元和星形胶质细胞共同参与抑郁症发生,胍丁胺可逆转慢性应激引起的细胞形态结构改变,发挥抗抑郁作用。     

百会穴针刺加灯盏花穴位注射对卒中后抑郁大鼠行为学的影响

目的观察百会穴针刺加灯盏花穴位注射对卒中后抑郁(PSD)大鼠行为学的影响。方法 SD雄性大鼠40只,随机分为空白组、PSD模型组、针刺穴注组、氟西汀组;后3组于大脑中动脉闭阻术(MCAO)后以慢性不可预见性温和应激刺激(CUMS)结合孤养法造成PSD模型。针刺穴注组予百会穴针刺加灯盏花注射液穴位注射治疗;氟西汀组予氟西汀水溶液灌胃治疗。观察各组大鼠旷野实验、蔗糖水偏嗜实验、强迫游泳实验。结果针刺穴注治疗和氟西汀治疗均能改善PSD大鼠运动活动性水平、兴趣高低、抑郁症状、绝望程度,针刺穴注组疗效优于氟西汀组。结论百会穴针刺加灯盏花穴位注射治疗PSD大鼠有效,可以显著改善其抑郁行为学异常,且疗效优于氟西汀。     

氟西汀调节TLR4/NF-κB/NLRP3炎症体信号通路改善CUMS大鼠抑郁样行为

目的 基于Toll样受体4(TLR4)/核因子κB(NF-κB)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症体信号通路探究氟西汀对慢性不可预知性轻度应激(CUMS)模型大鼠抑郁样行为的作用。方法 18只SD大鼠随机分为对照组、模型组和氟西汀组。模型组和氟西汀组大鼠随机给予不可预知性轻度刺激11周,制备抑郁症模型。氟西汀组于第7～11周灌胃氟西汀(10 mg·kg^-1·d^-1),其余组大鼠灌胃1 mL生理盐水。干预结束后进行行为学检测,酶联免疫吸附试验检测脑组织中白细胞介素(IL)-1β和IL-18的含量,免疫荧光染色观察海马CA3区和皮质区中NLRP3、凋亡相关斑点样蛋白(ASC)和胱天蛋白酶1(Caspase-1)的表达情况。Western blot测定脑组织TLR4、NF-κB、NLRP3、Caspase-1和活化的Caspase-1(cleaved Caspase-1)蛋白的表达水平。结果 与模型组比较,氟西汀组大鼠在旷场的运动距离及站立次数显著增多,在高架十字迷宫的运动距离增加,且在闭臂的停留时间减少,大鼠脑组织中IL-1β...     

氟西汀和度洛西汀联合奥氮平治疗伴自杀观念的抑郁症患者快速起效的对比研究

目的：探讨氟西汀联合奥氮平治疗伴自杀观念的抑郁症患者的疗效及起效时间。方法：选取我院接诊的伴自杀观念的抑郁症患者68例,随机分为观察组（n=34）和对照组（n=34）。观察组采用氟西汀联合奥氮平治疗,对照组采用盐酸度洛西汀联合奥氮平治疗。分析患者治疗不同时间的汉密尔顿抑郁量表（HAMD）和自杀意念自评量表（SSIOS）得分。结果：观察组治疗2周HAMD下降,治疗3d SSIOS得分下降,对照组治疗4周HAMD下降,治疗1周SSIOS得分下降,氟西汀联合奥氮平较盐酸度洛西汀联合奥氮平治疗起效更快（P＜0.05）。结论：氟西汀联合奥氮平治疗伴自杀观念的抑郁症患者的疗效好,起效时间短,值得临床推广。     

苏郁胶囊对双侧嗅球损伤抑郁模型大鼠行为学及下丘脑-垂体-肾上腺轴的影响

目的：探讨苏郁胶囊对双侧嗅球损伤抑郁模型大鼠行为学及下丘脑-垂体-肾上腺（HPA）轴的影响。方法：48只雄性大鼠随机分为假手术组、模型组、苏郁胶囊高、中、低剂量组（22．8、11．4、5．7g／kg）及氯米帕明组（0．02g／kg）。应用双侧嗅球损伤复制大鼠抑郁模型,敞箱法及跳台法测定大鼠的行为学指标;放射免疫方法测定大鼠血浆促肾上腺皮质素释放激素（CRH）、促肾上腺皮质激素（ACTH）及皮质醇（CORT）的水平。结果：苏郁胶囊可不同程度降低双侧嗅球损伤大鼠敞箱实验的水平运动次数与垂直运动次数;增加双侧嗅球损伤大鼠跳台实验的潜伏期及减少错误次数;同时降低双例嗅球损伤大鼠血浆CRH、ACTH和CORT含量。结论：苏郁胶囊能逆转双侧嗅球损伤抑郁模型大鼠的行为异常,其可能与苏郁胶囊有效地拮抗HPA轴功能亢进相关。     

噻奈普汀与氟西汀治疗抑郁症疗效与安全性分析

目的探讨了噻奈普汀与氟西汀治疗抑郁症疗效与安全性分析。方法 120例抑郁症患者随机分为两组,氟西汀组和噻奈普汀组,实验组60例,采用噻奈普汀进行治疗,氟西汀组患者60例,采用氟西汀进行治疗,治疗8周后,采用汉密尔顿抑郁量表对药物的治疗效果进行评价,采用不良反应量表对药物的不良反应进行评价。结果噻奈普汀组和氟西汀组的治疗有效率分别,两组相比较差异没有统计学意义(P<0.05)。两组患者在治疗2周后开始起效,噻奈普汀组在2、4和8周的汉密尔顿抑郁量减分率明显高于氟西汀组(P<0.05)。噻奈普汀组的主要毒副反应表现为口干、难以入睡、胃肠道反应、头痛、便秘等,与氟西汀组相比较,毒副作用明显较轻。结论 :噻奈普汀治疗对抑郁症疗效显著,毒副作用较低,优于氟西汀。     

氟西汀联合小剂量利培酮治疗62例伴躯体症状抑郁症患者的疗效分析

目的探讨氟西汀联合小剂量利培酮治疗伴躯体症状的抑郁症病人的效果。方法将62例符合CCMD-3伴躯体症状的抑郁症诊断标准的患者随机分为两组,分别给予氟西汀与氟西汀联合小剂量利培酮治疗,治疗时间为6周。结果应用氟西汀与利培酮联合治疗2周后,精神症状明显减轻;6周后总有效率为71%。结论作为增强剂利培酮可以提高氟西汀治疗伴躯体症状抑郁症的疗效。     

白香丹胶囊对经前期综合征肝气逆证模型大鼠学习记忆功能的影响

目的以经前期综合征(premenstrual syndrome,PMS)肝气逆证大鼠模型为载体考察白香丹胶囊对模型大鼠学习记忆功能的影响,探讨行为学表现下病证对学习记忆功能的损伤及白香丹胶囊的干预效应。方法应用情志刺激为主,多因素分段刺激法制备PMS肝气逆证大鼠模型并进行药物干预,采用旷场实验评价模型。采用Morris水迷宫、Y迷宫、新物体识别实验对PMS肝气逆证模型大鼠空间学习记忆能力和非空间学习记忆能力进行检测。结果与正常组大鼠相比,模型组大鼠总路程明显增加,进入中央区次数及中央区停留时间均明显降低;与模型组相比,白香丹组大鼠总路程明显下降,中央区停留时间及进入中央区次数均明显升高,氟西汀组大鼠总路程明显下降。与正常组相比,模型组大鼠分辨指数(distinguish index,DI)明显下降,白香丹组大鼠DI明显升高;定位航行阶段,与正常组大鼠相比,模型组大鼠在d 2、4逃避潜伏期明显上升;与模型组相比,白香丹和氟西汀组大鼠在d 2、4的逃避潜伏期明显降低;空间探索阶段,与正常组相比,模型组大鼠逃避潜伏期明显上升,而平台穿越次数明显减少,与模型组相比,白香丹组大鼠平台穿越次数明显增多。结论 PMS肝气逆证模型大鼠伴有学习记忆功能损伤,白香丹胶囊能够纠正模型大鼠的学习记忆功能缺陷,且治疗效果可能优于氟西汀。     

米氮平与氟西汀治疗抑郁症对照研究

目的探讨米氮平与氟西汀治疗抑郁症的疗效与安全性。方法将100例门诊和住院抑郁症患者随机为两组,分别给予米氮平和氟西汀治疗,疗程6周,于治疗前和治疗第1周、2周、4周、6周来采用汉密顿抑郁量(HAMD)、临床疗效总评量表(CGI)和副反应量表(TESS)评定临床疗效和不良反应。结果治疗6周末米氮平组总有效率91.5%,氟西组为89.6%,两组治疗各时段汉密顿抑郁量表及临床疗效总评量表评分均显著下降;米氮平组显效时间较氟西汀组快,药物不良反应明显少于氟西汀组。结论米氮平治疗抑郁症疗效好,起效快,依从性好,安全性高。     

米氮平与氟西汀治疗老年人抑郁症的对照研究

目的探讨米氮平与氟西汀治疗老年人抑郁症的疗效及安全性。方法将68例老年人抑郁症患者随机分为两组,研究组口服米氮平治疗,对照组口服氟西汀治疗,观察6周。与治疗前及治疗1周、2周、4周、6周末采取汉密顿抑郁量表评定临床疗效,副反应量表评定不良反应。结果米氮平治疗显效率为83.3%,氟西汀治疗显效率为76.7%,两组副作用方面无明显差异。结论米氮平治疗老年人抑郁症疗效与氟西汀相当,但起效较米氮平快,安全性高,适用于老年抑郁症患者。     

Chronic fluoxetine treatment attenuates stressor-induced changes in temperature, heart rate, and neuronal activation in the olfactory bulbectomized rat.

The olfactory bulbectomized (OB) rat is a well-characterized animal model that exhibits a number of behavioral and neurochemical changes that have relevance to clinical depression. Hyperactivity in the open field is the most widely used parameter assessed in this model and is reversed following chronic, but not acute, antidepressant treatment. This study investigated OB-induced alterations in heart rate, body temperature, and neuronal activation following open-field exposure and the impact of chronic treatment with fluoxetine on these parameters. Upon placement in the open field, OB rats exhibited a characteristic hyperactivity response. Heart rate and body temperature were increased in sham-operated rats following open-field exposure, a predictable response to stress, which was significantly reduced in OB rats. Moreover bulbectomy reduced open field-induced cFOS expression in the basal nucleus of the stria terminalis while concurrently increasing expression in the hippocampus, amygdala, paraventricular nucleus of the thalamus, and dorsal raphe nucleus. Chronic fluoxetine treatment (10 mg/kg subcutaneous once daily for 5 weeks) attenuated all of these OB-associated changes. In conclusion, OB rats exhibit alterations in behavior, body temperature, heart rate, and neuronal activation in response to open-field exposure, which are reversed following chronic fluoxetine administration. These results identify stress-sensitive regions within the brain which are altered following bulbectomy and which may underlie the abnormal behavioral and physiological changes observed in this rodent model of depression.     

Clinical and experimental studies on fluoxetine: effects on serotonin uptake

A decreased rate of uptake of serotonin (5HT) into platelets is recognized as a possible marker of the depressed state, being normalized only by effective antidepressant treatment. Fluoxetine is a novel antidepressant, with 5HT uptake inhibitory properties. In this study, treatment of depressed patients with fluoxetine for up to 6 months did not normalize the decreased platelet 5HT uptake rates associated with depression, although the patients showed a clinical recovery. The olfactory bulbectomized (OB) rat shows a characteristic hyperactivity in a stressful environment, which can be reversed only by chronic treatment with most antidepressants. OB rats have been found to exhibit a decreased rate of platelet 5HT uptake, similar to depressed patients, which is normalized by chronic antidepressant treatment. However, 3 weeks treatment with fluoxetine failed to reverse the hyperactivity of the OB rat and the decreased rates of uptake of 5HT. We also examined the rate of uptake of serotonin into the synaptosomes of the OB rats, in order to elucidate whether platelet 5HT uptake reflected central activity. Chronic fluoxetine treatment failed to normalize high affinity synaptosomal 5HT uptake in the OB rat. Fluoxetine, therefore, unlike most other antidepressants, does not normalize the decreased rates of platelet 5HT uptake in depressed patients on clinical recovery. OB rats also showed a deficit in their platelet and synaptosomal 5HT uptake rates, following 3 weeks treatment with fluoxetine.     

The determination of the optimal dose of milnacipran in the olfactory bulbectomized rat model of depression

Olfactory bulbectomy (OB) is associated with a variety of behavioral abnormalities such as hyperactivity in the "open-field" test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioral deficit. The activity of milnacipran (20, 30, and 40 mg/kg, PO bid) administered in two equally divided doses twice daily was assessed in the olfactory bulbectomized rat model of depression. It was found that chronic treatment with milnacipran at the doses of 30 and 40 mg/kg, but not 20 mg/kg, attenuated the lesion-induced hyperactivity of the OB rat in the "open-field" test following 14 days of treatment. In the step-through passive avoidance test, administration of milnacipran at doses of 20, 30, and 40 mg/kg had no effect on the performance deficit associated with olfactory bulbectomy. Olfactory bulbectomy reduced the concentration of noradrenaline (NA) in the frontal cortex. However, chronic milnacipran treatment did not significantly alter this deficit. It is concluded that milnacipran, when administered chronically at doses of 30 and 40 mg/kg, are effective at reversing the "open-field" deficit associated with olfactory bulbectomy, and that a dose of 30 mg/kg is an optimal dose.     

Evaluation of reward processes in an animal model of depression

Rationale Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.     

Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy

The olfactory bulbectomy (OB) is an animal model of depression that results in behavioral, neurochemical and neuroendocrinological changes, features comparable to those seen in depressive patients. This study investigated OB-induced alterations in locomotor activity and exploratory behavior in the open-field test, self-care and motivational behavior in the splash test, hyperactivity in the novel object test and novel cage test, and the influence of chronic treatment with fluoxetine (10 mg/kg, p.o., once daily for 14 days) on these parameters. Fluoxetine reversed OB-induced hyperactivity in the open-field test, locomotor hyperactivity and the increase in exploratory behavior induced by novelty in the novel object and novel cage tests, and the loss of self-care and motivational behavior in the splash test. Moreover, OB decreased the number of grooming and fecal boli in the open-field and novel cage tests, alterations that were not reversed by fluoxetine. OB caused an increase in hippocampal, but not in prefrontal acetylcholinesterase (AChE) activity. Fluoxetine was able to reverse the increase in hippocampal AChE activity induced by OB. Serum corticosterone was increased in SHAM and bulbectomized mice treated with fluoxetine. In conclusion, OB mice exhibited depressive-like behaviors associated with an increase in hippocampal AChE activity, effects that were reversed by chronic treatment with fluoxetine.     

Olfactory bulb ablation in the rat: behavioural changes and their reversal by antidepressant drugs.

1. The effects of bilateral olfactory bulbectomy, sham-operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability. 2. Bulbectomized rats were hyperactive, deficient at learning a step-down passive avoidance response and hyperirritable. Peripheral anosmia, induced by intranasal infusion of ZnSO4 solution resulted in no behavioural changes. 3. Chronic pretreatment with amitriptyline (3 and 10 mg/kg) and a tetracyclic antidepressant mianserin (Org GB 94, 5 and 15 mg/kg) reversed the hyperactivity and reduced the learning deficit of bulbectomized rats. These drugs had no significant effects on sham-operated animals. 4. Neither amitriptyline nor mianserin reduced the exaggerated responses of bulbectomized rats to external stimuli. 5. (+)-Amphetamine (1 and 3 mg/kg) accelerated the acquisition of the passive avoidance response, greatly enhanced the locomotor activity and slightly increased the irritability score of both sham-operated and bulbectomized rats. 6. Chlorpromazine (1 and 3 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the acquisition, locomotor activity and irritability of experimental and control rats. 7. Lithium sulphate (1 and 3 mg/kg) had no effect on activity or irritability but produced a small impairment in acquistion of bulbectomized rats. 8. It is concluded that the reversal by antidepressant drugs of the behavioural syndrome seen after olfactory bulb ablation could constitute a new model for the detection of this group of centrally acting compounds.     

The effects of fluoxetine and zimeldine on the behavior of olfactory bulbectomized rats

Previous work has shown that subchronic administration of antidepressant drugs can reverse the behavioral and physiological changes produced by removal of the olfactory bulbs of rats. It has also been reported that acute administration of drugs believed to enhance serotonergic transmission can improve passive avoidance performance in bulbectomized rats. In order to follow up this observation the effects of the serotonin reuptake inhibitor, fluoxetine, were studied in bulbectomized and control rats. Fluoxetine produced a dose-related improvement in the passive avoidance behavior of bulbectomized rats in a step-down task and in a Y-maze. The effect of fluoxetine on step-down avoidance was blocked by metergoline and was also shown by zimeldine, another inhibitor of serotonin reuptake. However, in tests of active avoidance responding in a shuttle box and exploratory locomotion, fluoxetine produced similar disruptions of behavior in both bulbectomized and control animals. Thus, the effects of fluoxetine on the behavior of bulbectomized rats are dependent upon the behavioral test.     

Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates

1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes.
2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy.
3. The B_max value of [³H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls.
4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats.
5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections.
6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.

     

Olfactory bulbectomy increases met-enkephalin- and neuropeptide-Y-like immunoreactivity in rat limbic structures

Bilateral olfactory bulbectomy (OBX) in rats produces a well-characterized syndrome of behavioral, physiological, and neurochemical changes identical to those seen in depression. Previous experiments using in situ hybridization histochemistry have demonstrated that OBX increases prepro-neuropeptide-Y (NPY) and prepro-enkephalin (ENK) mRNA levels in limbic structures. The present experiments determined whether increases in peptide immunoreactivity occur in conjunction with increases in mRNA levels following OBX. In situ hybridization analyses in olfactory bulbectomized and sham-operated rats revealed increased prepro-ENK mRNA in the piriform cortex (PIR) and olfactory tubercles (OTs) of bulbectomized rats. Prepro-NPY mRNA levels were significantly increased in the PIR of bulbectomized rats as comapred to controls. Radioimmunoassays (RIAs) revealed significant elevations in ENK-like immunoreactivity in the OTs following OBX. NPY-like immunoreactivity was significantly elevated in the PIR following OBX. These data reveal that OBX-induced increases in ENK-like immunoreactivity occur concomitantly with increases in prepro-ENK mRNA, and NPY-like immunoreactivity occur concomitantly with increases in prepro-NPY mRNA.     

Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour.

1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.