Fluvoxamine reverses estrogen-dependent decline in voluntary activities and decreased amygdala levels of serotonin in ovariectomized rats

Yukiko Ishibashi, N. Izumo, K. Iwata, Tomomi Morikawa, T. Kameyama, Yasuo Watanabe, T. Manabe, Hideo Matsuzaki
{"title":"Fluvoxamine reverses estrogen-dependent decline in voluntary activities and decreased amygdala levels of serotonin in ovariectomized rats","authors":"Yukiko Ishibashi, N. Izumo, K. Iwata, Tomomi Morikawa, T. Kameyama, Yasuo Watanabe, T. Manabe, Hideo Matsuzaki","doi":"10.20821/JBS.46.0_5","DOIUrl":null,"url":null,"abstract":"Studies suggest that increased expression of brain-derived neurotrophic factor (BDNF) could mediate the antidepressant effects of drugs. We analyzed the effects of fluvoxamine on locomotor activities, serotonin levels in the amygdala, and hippocampal expression of BDNF mRNA in ovariectomized (OVX) rats. Female Wistar rats (8 weeks, 180–200 g) were divided into four groups: sham; OVX; OVX with estrogen; and OVX with fluvoxamine. Six weeks after ovariectomy, rats were assessed according to spontaneous locomotor activity, forced-swimming test (FST), and microdialyses experiments. Body and uterine weight of OVX rats 6 weeks after surgery were significantly increased and decreased, respectively, compared with those of the sham group, but these changes were returned to sham-group levels upon chronic administration of estrogen and fluvoxamine. More potent decreases in voluntary activities were observed in OVX rats compared with rats in the sham group, but were increased markedly upon administration of estrogen and fluvoxamine. In the FST, immobility time and beat counts were increased and decreased significantly by ovariectomy compared with those of the sham group, respectively, but estrogen and fluvoxamine treatment reversed these changes significantly. More potent decreases in serotonin release in the amygdala were observed in OVX rats compared with those of sham rats, but were reversed upon estrogen Journal of Brain Science, June 30, 2016,Vol.46 7 replacement. Similar recovery was observed in OVX rats upon fluvoxamine treatment. These data suggest that, in OVX rats, chronic administration of fluvoxamine can recover estrogen-dependent changes in behaviors, decreased serotonin release in the amygdala, and reduced expression of BDNF mRNA. Key wards: Amygdala, Serotonin, Estrogen, Fluvoxamine, OVX; Abbreviations BDNF, brain-derived neurotrophic factor; ER, endoplasmic reticulum; OVX, ovariectmized; RT-PCR, reverse transcription-polymerase chain reaction; SSRI, selective serotonin reuptake inhibitor; XBP-1, X-box binding protein-1; mRNA, messenger ribonucleic acid Introduction The female hormone estrogen has an important role in bone physiology (reviewed in [15, 16]). Moreover, there is a close relationship between estrogen and memory, learning, and emotion in the brain (reviewed in [16]). Also, it has been reported that replenishment with estrogen can improve recognition, learning and memory (reviewed in [3, 5, 14]). We reported that, in female rats 6 weeks after their ovaries had been removed, depression-like symptoms (as manifested by decreases in spontaneous locomotor activities and serotonin levels in the amygdala) could be observed [9]. Depression is a complex disorder brought about by genetic and environmental conditions. Depression involves brain abnormalities as well as dysfunction of the endocrine system, inflammation, altered glucose metabolism and, in some cases, coronary artery disease [8, 18]. Selective serotonin reuptake inhibitors (SSRIs) are first-line treatment for depression and depression-like symptoms. However, resistance to the effects of antidepressants has been documented, so development of new agents with new mechanisms of action is needed [13]. Journal of Brain Science, June 30, 2016,Vol.46 8 Studies have suggested that brain-derived neurotrophic factor (BDNF) signaling is necessary and sufficient for the action of antidepressant drugs [20]. BDNF signaling is associated with cyclic adenosine monophosphate responsive element binding protein, which induces neurogenesis [20]. Moreover, high levels of BDNF have been observed in post mortem hippocampal samples from individuals suffering from depression [20]. Such findings suggest a correlation between decreased expression of BDNF and the onset of depression. Furthermore, a recent report demonstrated that the SSRI fluvoxamine reversed the reduced expression of BDNF messenger ribonucleic acid (mRNA) by chronic infusion of dexamethasone in mice exhibiting depression-like behaviors [17]. Therefore, the therapeutic effects of antidepressants could be mediated by increased expression of BDNF. In the present study, we analyzed the chronic (6-week) effects of the antidepressant fluvoxamine on locomotor activities, serotonin levels in the amygdala, and expression of BDNF mRNA in the hippocampus in ovariectomized (OVX) rats. Materials and Methods Ethical approval of the study protocol The study protocol was approved by the Ethics Committee of Yokohama College of Pharmacy (Kanagawa, Japan). All experiments using animals were carried out based on Guidelines for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA) as approved by the Japanese Pharmacological Society. Animals, ovariectomy, and drug administration Animal care and ovariectomy were as described previously with minor modification [9]. Briefly, 36 female Wistar rats (8 weeks, 180–200 g) were divided into four groups of nine. Rats were allowed to acclimatize for ≥1 week to their surroundings before the start of experimentation (12-h light–dark cycle; Journal of Brain Science, June 30, 2016,Vol.46 9 lights on at 7 am and off at 7 pm). After 1 week, OVX and sham operations were undertaken as described previously (Fukushima et al., 2000). One week after ovariectomy, fluvoxamine (50 mg/kg body weight; Wako Pure Chemical Industries, Osaka, Japan) and β-estradiol (50 μg/kg body weight; Sigma–Aldrich, Saint Louis, MO, USA) were administered (p.o. and i.p., respectively) five times per week for 6 weeks. Voluntary momentum, forced-swim test (FST), and microdialyses Six weeks after ovariectomy, rats were assessed according to spontaneous locomotor activity, FST, and microdialyses experiments, as described previously [9, 17]. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) RT-PCR was carried out as described previously [17]. Statistical analyses Statistical analyses were undertaken as described previously [17]. Results Body weight and uterine weight of OVX rats 6 weeks after surgery were increased and decreased significantly, respectively, compared with that of the sham group (Fig. 1a and b; sham and OVX groups). The increased body weight and decreased uterine weight of OVX rats returned to sham-group levels upon chronic administration of estrogen (Fig. 1a and b; sham and estrogen groups). A tendency for recovery was observed upon chronic administration of fluvoxamine in terms of increases and decreases of body weight and uterine weight, but the differences were not significant (Fig 1a and b; sham and fluvoxamine groups). Figure 2a shows spontaneous locomotor activity for 12 h in the dark phase (7 pm to 7 am) for the four groups 6 weeks after ovariectomy. More potent decreases in voluntary activities were observed in OVX rats compared with rats in the sham group (Fig. 2b). These Journal of Brain Science, June 30, 2016,Vol.46 10 data were similar to those of our previous report [9]. These decreases in locomotor activities in OVX rats in the dark phase were increased markedly upon administration of estrogen and fluvoxamine (Fig. 2b). Next, we analyzed the immobility time and beat counts on FST of the four rat groups (Fig. 3). Immobility time and beat counts were increased and decreased significantly by ovariectomy compared with those of the sham group, respectively (Fig. 3a and b; sham and OVX groups). These data were consistent with our previous report [9]. Treatment with estrogen and fluvoxamine reversed these changes significantly to levels seen in control rats (Figs. 3a and b). Next, we analyzed serotonin levels in the amygdala under identical conditions (Fig. 4). More potent decreases in serotonin release in the amygdala were observed in OVX rats compared with those of sham rats (Fig. 4a). These observations were consistent with our previous report [9]. These decreases in serotonin levels in the amygdala were reversed upon estrogen replacement (Fig. 4a; OVX and estrogen), suggesting that decreases in serotonin level by ovariectomy were dependent upon the disappearance of estrogen. A similar recovery was observed in OVX rats upon fluvoxamine treatment (Fig. 4a; OVX and fluvoxamine). However, this recovery in serotonin release was not detected in the case of dopamine release in the amygdala (Fig. 4b). This result was expected because SSRIs have a mechanism of action specific for serotonin. Next, we analyzed hippocampal BDNF expression of sham rats and OVX rats using RT-PCR (Fig. 5). No significant changes were observed in samples from any group obtained from the cerebral cortex or brainstem (Fig. 5; middle and lower panels). More potent decreases in hippocampal BDNF expression were observed in the OVX group compared with that in sham Journal of Brain Science, June 30, 2016,Vol.46 11 groups (Fig. 5; upper panel). This elevation of BDNF expression was recovered markedly upon estrogen treatment (Fig. 5; upper panel). Hippocampal BDNF expression in OVX rats was recovered significantly upon fluvoxamine treatment (Fig. 5; upper panel). Hippocampal expression of the estrogen receptor-1 gene was not changed in all groups (data not shown). Discussion The present study showed that the body weight and uterine weight of OVX rats 6 weeks after ovariectomy were increased and decreased significantly compared with that of the sham group, respectively (Fig. 1), and that this phenomenon was consistent with previous reports [1,4,9]. These results suggest that we carried out ovariectomy successfully. Such increases in body weight and decreases in uterine weight in OVX rats were returned to sham-group levels upon chronic administration of estrogen (Fig. 1), suggesting that the increased weight of OVX rats was significantly dependent upon disappearance of estrogen. Moreover, this tendency for recovery in increases and decreases in body weight and uterine weight was also observed upon chronic administration of fluvoxamine except that the differences were not significant (Fig.","PeriodicalId":15186,"journal":{"name":"Journal of Behavioral and Brain Science","volume":"24 1","pages":"5-19"},"PeriodicalIF":0.0000,"publicationDate":"2016-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Behavioral and Brain Science","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.20821/JBS.46.0_5","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1

Abstract

Studies suggest that increased expression of brain-derived neurotrophic factor (BDNF) could mediate the antidepressant effects of drugs. We analyzed the effects of fluvoxamine on locomotor activities, serotonin levels in the amygdala, and hippocampal expression of BDNF mRNA in ovariectomized (OVX) rats. Female Wistar rats (8 weeks, 180–200 g) were divided into four groups: sham; OVX; OVX with estrogen; and OVX with fluvoxamine. Six weeks after ovariectomy, rats were assessed according to spontaneous locomotor activity, forced-swimming test (FST), and microdialyses experiments. Body and uterine weight of OVX rats 6 weeks after surgery were significantly increased and decreased, respectively, compared with those of the sham group, but these changes were returned to sham-group levels upon chronic administration of estrogen and fluvoxamine. More potent decreases in voluntary activities were observed in OVX rats compared with rats in the sham group, but were increased markedly upon administration of estrogen and fluvoxamine. In the FST, immobility time and beat counts were increased and decreased significantly by ovariectomy compared with those of the sham group, respectively, but estrogen and fluvoxamine treatment reversed these changes significantly. More potent decreases in serotonin release in the amygdala were observed in OVX rats compared with those of sham rats, but were reversed upon estrogen Journal of Brain Science, June 30, 2016,Vol.46 7 replacement. Similar recovery was observed in OVX rats upon fluvoxamine treatment. These data suggest that, in OVX rats, chronic administration of fluvoxamine can recover estrogen-dependent changes in behaviors, decreased serotonin release in the amygdala, and reduced expression of BDNF mRNA. Key wards: Amygdala, Serotonin, Estrogen, Fluvoxamine, OVX; Abbreviations BDNF, brain-derived neurotrophic factor; ER, endoplasmic reticulum; OVX, ovariectmized; RT-PCR, reverse transcription-polymerase chain reaction; SSRI, selective serotonin reuptake inhibitor; XBP-1, X-box binding protein-1; mRNA, messenger ribonucleic acid Introduction The female hormone estrogen has an important role in bone physiology (reviewed in [15, 16]). Moreover, there is a close relationship between estrogen and memory, learning, and emotion in the brain (reviewed in [16]). Also, it has been reported that replenishment with estrogen can improve recognition, learning and memory (reviewed in [3, 5, 14]). We reported that, in female rats 6 weeks after their ovaries had been removed, depression-like symptoms (as manifested by decreases in spontaneous locomotor activities and serotonin levels in the amygdala) could be observed [9]. Depression is a complex disorder brought about by genetic and environmental conditions. Depression involves brain abnormalities as well as dysfunction of the endocrine system, inflammation, altered glucose metabolism and, in some cases, coronary artery disease [8, 18]. Selective serotonin reuptake inhibitors (SSRIs) are first-line treatment for depression and depression-like symptoms. However, resistance to the effects of antidepressants has been documented, so development of new agents with new mechanisms of action is needed [13]. Journal of Brain Science, June 30, 2016,Vol.46 8 Studies have suggested that brain-derived neurotrophic factor (BDNF) signaling is necessary and sufficient for the action of antidepressant drugs [20]. BDNF signaling is associated with cyclic adenosine monophosphate responsive element binding protein, which induces neurogenesis [20]. Moreover, high levels of BDNF have been observed in post mortem hippocampal samples from individuals suffering from depression [20]. Such findings suggest a correlation between decreased expression of BDNF and the onset of depression. Furthermore, a recent report demonstrated that the SSRI fluvoxamine reversed the reduced expression of BDNF messenger ribonucleic acid (mRNA) by chronic infusion of dexamethasone in mice exhibiting depression-like behaviors [17]. Therefore, the therapeutic effects of antidepressants could be mediated by increased expression of BDNF. In the present study, we analyzed the chronic (6-week) effects of the antidepressant fluvoxamine on locomotor activities, serotonin levels in the amygdala, and expression of BDNF mRNA in the hippocampus in ovariectomized (OVX) rats. Materials and Methods Ethical approval of the study protocol The study protocol was approved by the Ethics Committee of Yokohama College of Pharmacy (Kanagawa, Japan). All experiments using animals were carried out based on Guidelines for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA) as approved by the Japanese Pharmacological Society. Animals, ovariectomy, and drug administration Animal care and ovariectomy were as described previously with minor modification [9]. Briefly, 36 female Wistar rats (8 weeks, 180–200 g) were divided into four groups of nine. Rats were allowed to acclimatize for ≥1 week to their surroundings before the start of experimentation (12-h light–dark cycle; Journal of Brain Science, June 30, 2016,Vol.46 9 lights on at 7 am and off at 7 pm). After 1 week, OVX and sham operations were undertaken as described previously (Fukushima et al., 2000). One week after ovariectomy, fluvoxamine (50 mg/kg body weight; Wako Pure Chemical Industries, Osaka, Japan) and β-estradiol (50 μg/kg body weight; Sigma–Aldrich, Saint Louis, MO, USA) were administered (p.o. and i.p., respectively) five times per week for 6 weeks. Voluntary momentum, forced-swim test (FST), and microdialyses Six weeks after ovariectomy, rats were assessed according to spontaneous locomotor activity, FST, and microdialyses experiments, as described previously [9, 17]. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) RT-PCR was carried out as described previously [17]. Statistical analyses Statistical analyses were undertaken as described previously [17]. Results Body weight and uterine weight of OVX rats 6 weeks after surgery were increased and decreased significantly, respectively, compared with that of the sham group (Fig. 1a and b; sham and OVX groups). The increased body weight and decreased uterine weight of OVX rats returned to sham-group levels upon chronic administration of estrogen (Fig. 1a and b; sham and estrogen groups). A tendency for recovery was observed upon chronic administration of fluvoxamine in terms of increases and decreases of body weight and uterine weight, but the differences were not significant (Fig 1a and b; sham and fluvoxamine groups). Figure 2a shows spontaneous locomotor activity for 12 h in the dark phase (7 pm to 7 am) for the four groups 6 weeks after ovariectomy. More potent decreases in voluntary activities were observed in OVX rats compared with rats in the sham group (Fig. 2b). These Journal of Brain Science, June 30, 2016,Vol.46 10 data were similar to those of our previous report [9]. These decreases in locomotor activities in OVX rats in the dark phase were increased markedly upon administration of estrogen and fluvoxamine (Fig. 2b). Next, we analyzed the immobility time and beat counts on FST of the four rat groups (Fig. 3). Immobility time and beat counts were increased and decreased significantly by ovariectomy compared with those of the sham group, respectively (Fig. 3a and b; sham and OVX groups). These data were consistent with our previous report [9]. Treatment with estrogen and fluvoxamine reversed these changes significantly to levels seen in control rats (Figs. 3a and b). Next, we analyzed serotonin levels in the amygdala under identical conditions (Fig. 4). More potent decreases in serotonin release in the amygdala were observed in OVX rats compared with those of sham rats (Fig. 4a). These observations were consistent with our previous report [9]. These decreases in serotonin levels in the amygdala were reversed upon estrogen replacement (Fig. 4a; OVX and estrogen), suggesting that decreases in serotonin level by ovariectomy were dependent upon the disappearance of estrogen. A similar recovery was observed in OVX rats upon fluvoxamine treatment (Fig. 4a; OVX and fluvoxamine). However, this recovery in serotonin release was not detected in the case of dopamine release in the amygdala (Fig. 4b). This result was expected because SSRIs have a mechanism of action specific for serotonin. Next, we analyzed hippocampal BDNF expression of sham rats and OVX rats using RT-PCR (Fig. 5). No significant changes were observed in samples from any group obtained from the cerebral cortex or brainstem (Fig. 5; middle and lower panels). More potent decreases in hippocampal BDNF expression were observed in the OVX group compared with that in sham Journal of Brain Science, June 30, 2016,Vol.46 11 groups (Fig. 5; upper panel). This elevation of BDNF expression was recovered markedly upon estrogen treatment (Fig. 5; upper panel). Hippocampal BDNF expression in OVX rats was recovered significantly upon fluvoxamine treatment (Fig. 5; upper panel). Hippocampal expression of the estrogen receptor-1 gene was not changed in all groups (data not shown). Discussion The present study showed that the body weight and uterine weight of OVX rats 6 weeks after ovariectomy were increased and decreased significantly compared with that of the sham group, respectively (Fig. 1), and that this phenomenon was consistent with previous reports [1,4,9]. These results suggest that we carried out ovariectomy successfully. Such increases in body weight and decreases in uterine weight in OVX rats were returned to sham-group levels upon chronic administration of estrogen (Fig. 1), suggesting that the increased weight of OVX rats was significantly dependent upon disappearance of estrogen. Moreover, this tendency for recovery in increases and decreases in body weight and uterine weight was also observed upon chronic administration of fluvoxamine except that the differences were not significant (Fig.
氟伏沙明逆转卵巢切除大鼠自愿活动的雌激素依赖性下降和杏仁核血清素水平下降
研究表明,脑源性神经营养因子(BDNF)的表达增加可能介导药物的抗抑郁作用。我们分析了氟伏沙明对去卵巢(OVX)大鼠运动活动、杏仁核血清素水平和海马BDNF mRNA表达的影响。雌性Wistar大鼠(8周,180 ~ 200 g)分为4组:假手术组;OVX;OVX加雌激素;用氟伏沙明和OVX切除卵巢6周后,根据自主运动活动、强迫游泳试验(FST)和微透析实验对大鼠进行评估。术后6周,OVX大鼠的体重和子宫重量分别较假手术组明显增加和减少,但经长期给予雌激素和氟伏沙明后,这些变化又恢复到假手术组的水平。与假手术组的大鼠相比,OVX大鼠的自愿活动明显减少,但在给予雌激素和氟伏沙明后明显增加。在FST中,与假手术组相比,卵巢切除术后静止时间和心跳计数分别显著增加和减少,但雌激素和氟伏沙明治疗可显著逆转这些变化。与假手术大鼠相比,OVX大鼠杏仁核中血清素释放的减少更明显,但在雌激素作用下则相反。46 .更换。在氟伏沙明治疗的OVX大鼠中也观察到类似的恢复。这些数据表明,在OVX大鼠中,长期给予氟伏沙明可以恢复雌激素依赖的行为改变,减少杏仁核中血清素的释放,降低BDNF mRNA的表达。关键词:杏仁核,血清素,雌激素,氟伏沙明,OVX;脑源性神经营养因子;内质网;OVX ovariectmized;逆转录聚合酶链反应;选择性血清素再摄取抑制剂;XBP-1, X-box结合蛋白1;雌性激素雌激素在骨生理中具有重要作用(综述于[15,16])。此外,雌激素与大脑中的记忆、学习和情绪之间存在密切关系(见b[16])。此外,有报道称补充雌激素可以改善认知、学习和记忆(参见[3,5,14])。我们报道,在雌性大鼠卵巢切除6周后,可以观察到抑郁样症状(表现为自发运动活动和杏仁核血清素水平下降)[9]。抑郁症是一种由遗传和环境条件引起的复杂疾病。抑郁症包括脑异常以及内分泌系统功能障碍、炎症、葡萄糖代谢改变,在某些情况下还包括冠状动脉疾病[8,18]。选择性血清素再摄取抑制剂(SSRIs)是治疗抑郁症和抑郁样症状的一线药物。然而,抗抑郁药的耐药性已被证实,因此需要开发具有新的作用机制的新药物。脑科学杂志,2016年6月30日,卷。研究表明,脑源性神经营养因子(BDNF)信号传导对于抗抑郁药物[20]的作用是必要和充分的。BDNF信号通路与单磷酸环腺苷反应元件结合蛋白相关,可诱导神经发生[20]。此外,在患有抑郁症的人的死后海马样本中观察到高水平的BDNF。这些发现表明BDNF表达减少与抑郁症发病之间存在相关性。此外,最近的一份报告表明,SSRI氟伏沙明通过长期注射地塞米松逆转了表现出抑郁样行为的小鼠BDNF信使核糖核酸(mRNA)表达的减少。因此,抗抑郁药物的治疗效果可能是通过BDNF表达增加介导的。在本研究中,我们分析了抗抑郁药氟伏沙明对去卵巢(OVX)大鼠运动活动、杏仁核血清素水平和海马BDNF mRNA表达的慢性(6周)影响。材料与方法研究方案的伦理批准本研究方案经横滨药学院(神奈川,日本)伦理委员会批准。所有动物实验均根据日本药理学会批准的《实验动物护理和使用指南》(美国国立卫生研究院Bethesda, MD, USA)进行。动物、卵巢切除和药物管理动物护理和卵巢切除与前面描述的一样,只是做了一些修改。将36只雌性Wistar大鼠(8周,180 ~ 200 g)分为4组,每组9只。 实验开始前,让大鼠适应环境≥1周(12 h明暗循环;脑科学杂志,2016年6月30日,卷。(早上7点开,晚上7点关)。1周后,如前所述进行OVX和假手术(Fukushima et al., 2000)。卵巢切除术后1周,氟伏沙明(50 mg/kg体重;Wako Pure Chemical Industries,大阪,日本)和β-雌二醇(50 μg/kg体重;Sigma-Aldrich, st . Louis, MO, USA)每周给药5次(分别为p.o.和i.p.),持续6周。卵巢切除术后6周,根据自主运动活动、FST和微透析实验对大鼠进行评估,如前所述[9,17]。定量逆转录聚合酶链反应(RT-PCR) RT-PCR按照先前描述的方法进行。统计分析按前面所述进行统计分析。结果OVX大鼠术后6周体重与假手术组比较,体重明显增加,子宫重量明显减少(图1a、b;sham组和OVX组)。长期给药后,OVX大鼠的体重增加和子宫重量减少恢复到假组水平(图1a和b;假手术组和雌激素组)。在体重和子宫重量的增加和减少方面,慢性服用氟伏沙明有恢复的趋势,但差异不显著(图1a和b;假手术组和氟伏沙明组)。图2a显示了卵巢切除6周后四组在黑暗期(晚上7点至早上7点)12小时的自发运动活动。与假手术组相比,OVX大鼠的自愿活动减少更明显(图2b)。《脑科学杂志》,2016年6月30日,卷。46 10数据与我们之前的报告b[9]相似。在雌激素和氟伏沙明的作用下,OVX大鼠在暗期运动活动的减少明显增加(图2b)。接下来,我们分析了四组大鼠FST的静止时间和心跳计数(图3)。与假手术组相比,卵巢切除术后静止时间和心跳计数分别显著增加和减少(图3a和b;sham组和OVX组)。这些数据与我们之前的报告b[9]一致。雌激素和氟伏沙明治疗使这些变化明显逆转到对照大鼠的水平(图3a和b)。接下来,我们分析了相同条件下杏仁核中的血清素水平(图4)。与假手术大鼠相比,OVX大鼠杏仁核中血清素释放的减少更明显(图4a)。这些观察结果与我们以前的报告b[9]一致。在雌激素替代后,杏仁核中血清素水平的下降被逆转(图4a;卵巢切除术后血清素水平的降低依赖于雌激素的消失。在氟伏沙明治疗的OVX大鼠中观察到类似的恢复(图4a;OVX和氟伏沙明)。然而,在杏仁核多巴胺释放的情况下,没有检测到血清素释放的恢复(图4b)。这一结果是意料之中的,因为SSRIs具有针对血清素的特异性作用机制。接下来,我们使用RT-PCR分析假手术大鼠和OVX大鼠的海马BDNF表达(图5)。从大脑皮层或脑干获得的任何组的样本均未观察到显著变化(图5;中下面板)。与sham组相比,OVX组海马BDNF表达的下降更明显。46 11组(图5;上半部分)。这种BDNF表达的升高在雌激素治疗后明显恢复(图5;上半部分)。经氟伏沙明治疗后,OVX大鼠海马BDNF表达显著恢复(图5;上半部分)。各组海马雌激素受体-1基因表达均无变化(数据未显示)。本研究显示,卵巢切除6周后,OVX大鼠的体重和子宫重量分别较假手术组明显增加和减少(图1),这一现象与文献报道一致[1,4,9]。这些结果表明我们成功地进行了卵巢切除术。长期给药后,OVX大鼠体重的增加和子宫重量的减少恢复到假组水平(图1),表明OVX大鼠体重的增加明显依赖于雌激素的消失。 此外,在长期服用氟伏沙明后,体重和子宫重量的增加和减少也有恢复的趋势,但差异不显著(图2)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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