神经肽在动物抑郁症发生发展中的作用研究
|
摘要
抑郁症是指以情绪情感的剧烈变化和心境持续恶劣为主要特征的一类心境障碍疾病。抑郁症的患病率逐年增加并呈现年轻化趋势,对个人健康、社会秩序和经济均造成严重的影响。联合国世界卫生组织预测,到2020年抑郁症将成为导致人类死亡和残疾的第2大疾病。抑郁症的病因错综复杂、症状多态,其发病机制至今尚不完全清楚。应激导致HPA轴功能亢进,进而引起单胺类神经递质系统功能下降而引发抑郁症成为目前主要的病因学说。但围绕单胺类递质设计的抗抑郁药存在特异性较差,药物相互作用,具有一定的副作用以及长期应用易产生耐受性等缺点。特异性更强的直接作用于相关受体的一类新型抗抑郁药物成为近年开发研究的热点。神经肽是一类传递信息的多肽,广泛存在于神经系统和机体各部位,参与应激反应、心血管活动等多种功能的调节。神经肽对神经递质代谢与功能具有重要的影响,被认为是单胺类神经递质的上游调节因子,其在抑郁症发病过程中所起的作用正在引起强烈关注。
本论文研究的第一部分工作:采用强迫游泳、悬尾、慢性未预知应激和嗅球切除手段分别建立抑郁症大鼠模型,运用旷场行为实验(open-field behavior)检测大鼠主动性活动能力,通过测量糖水消耗量观察大鼠幸福感和奖赏程度,用Morris水迷宫法检测大鼠空间学习记忆能力,HPLC-UV法测定大鼠血清皮质酮含量。结果显示,与对照组相比,慢性应激和嗅球切除两种建模方式均使大鼠的体重增量明显降低,糖水消耗量显著减少,主动性活动能力和空间探索欲望明显下降,血清皮质酮含量显著升高,空间学习和短时记忆能力明显降低,对大鼠空间记忆的长时保持能力的影响则不显著。而强迫游泳和悬尾两种建模方式对大鼠的体重增量、糖水消耗量、主动性活动能力和空间探索欲望、血清皮质酮含量以及空间学习和短时记忆能力的影响都不明显。以上结果表明,慢性应激和嗅球切除两种建模方式可使大鼠表现出明显的抑郁症特征,在多种评价指标上有着一致性,是较理想的建模手段;而单一的强迫游泳或悬尾可能使动物对同一种刺激产生适应,建模效果不佳。
研究的第二部分工作:采用慢性未预知应激建立抑郁症大鼠模型,运用基因芯片、RT-PCR和荧光定量PCR技术检测大鼠下丘脑、中缝背核和海马脑区神经肽及其受体的表达。结果显示,应激模型大鼠下丘脑、中缝背核、海马三个脑区的CRF及其受体R1 mRNA的表达量都明显增加。除了GALR1在下丘脑及海马表达减少外,GAL及其受体GALR1及GALR2在下丘脑、中缝背核、海马三个脑区的表达均显著增加。NPY及其受体NPYR1,NPYR2和NPYR5在三个脑区的表达都明显上升。除了AVP在海马脑区表达差异不显著外,AVP及其受体AVPR1a和AVPR1b在以上三个脑区的表达也都明显增加。以上结果表明,在抑郁症发生发展过程中,CRF、GAL和NPY很可能参与了神经元功能的调节。
第三部分的研究工作对CRF、GAL和NPY在抑郁症形成中的作用分别进行功能验证。1.正常大鼠侧脑室慢性注射CRF 21天并与慢性非预见性应激刺激21天建立的抑郁症模型大鼠进行比较。2.慢性应激模型大鼠侧脑室分别慢性注射GAL、GAL2-11(受体2的特异性激动剂)以及NPY与应激模型大鼠侧脑室注射aCSF进行比较。运用旷场行为实验(open-field behavior)观察大鼠主动性活动能力,采用Morris水迷宫法,以训练期的逃避潜伏期为指标检测大鼠空间学习记忆能力。结果显示,1.正常大鼠侧脑室慢性注射CRF 21天之后,其体重增量、主动性活动和学习记忆能力与慢性应激模型大鼠一样均明显下降。2.大鼠慢性应激建模成功后,侧脑室分别慢性注射GAL、GAL2-11以及NPY,其主动性活动能力均显著提高。未建模大鼠侧脑室慢性注射GAL,主动性活动没有显著的变化。另外,GAL2-11可使抑郁症大鼠的学习能力明显改善,GAL、NPY的效果则不明显。以上结果说明,慢性应激导致机体CRF分泌持续增加可能是抑郁症发病的直接原因。抑郁症形成过程中,GAL及其受体2(GALR2)的高表达,NPY系统的表达上调可能都是机体的保护性调节。通过CRF受体R1,GAL受体2以及NPY系统探寻抗抑郁药物靶点和开发新药,具有广阔前景。
研究的第四部分工作探讨CRF及皮质酮在海马相关的抑郁症发生机制中的作用。1.采用慢性应激和嗅球切除两种抑郁症模型大鼠,运用电生理方法,诱导并记录大鼠海马CA1区LTP与LTD场兴奋性突触后电位(f-EPSP),观察海马突触可塑性。用HPLC-FLU法检测大鼠海马脑区5-HT,NE两种神经递质含量。2.运用光学显微镜和透射电子显微镜技术观察慢性应激、嗅球切除和侧脑室慢性注射CRF对大鼠海马神经细胞结构的影响。3.通过离体培养的大鼠海马神经细胞,分别观察CRF和皮质酮对海马神经细胞的作用模式。结果显示,1.两种模型大鼠海马CA1区诱导LTP和LTD的能力明显低于相应对照组,海马突触可塑性均显著降低;海马脑区的5—HT含量明显减少,NE含量变化不大,单胺类神经递质含量出现紊乱。2.慢性应激、嗅球切除和侧脑室慢性注射CRF三种方式均能引起大鼠海马神经细胞结构严重损伤,细胞核固缩或溶解,细胞质及线粒体内部出现空洞化,线粒体肿胀、嵴断裂,数量减少;突触稀疏,突触后膜增厚。3.连续加药9天,不同浓度的CRF对离体海马神经细胞的存活率没有明显的影响。连续作用7天,与对照组比较,低浓度(10~(-8)mol/L)的皮质酮对海马神经细胞有一定的保护作用,当浓度大于一定数值(10~(-7)mol/L)时,则反映出浓度相关的损伤效应。以上结果提示,应激首先作用于海马,引起CRF释放,使大量糖皮质激素(GC)产生并释放,导致机体皮质醇(酮)含量增加,后者直接损伤海马神经细胞结构,细胞坏死或凋亡,海马容积变小,最终导致其控制学习记忆和调节情绪的功能衰退,直至形成抑郁。
结论:
1.慢性应激和嗅球切除两种建模方式可使大鼠表现出明显的抑郁症特征,在多种评价指标上有着一致性,是较理想的建模手段;
2.慢性应激导致机体CRF分泌持续增加可能是抑郁症发病的直接原因。抑郁症形成过程中,GAL及其受体2(GALR2)的高表达,NPY系统的表达上调都可能是机体的保护性调节。通过CRF受体R1,GAL受体2以及NPY系统探寻抗抑郁药物靶点和开发新药,具有广阔前景;
3.应激刺激引起海马脑区的实质性损伤,提示应激刺激首先引起机体下丘脑CRF的分泌和导致HPA轴功能亢进,导致糖皮质激素急剧升高,皮质醇(酮)含量增加。后者直接损伤海马神经细胞结构,细胞坏死或凋亡,海马容积变小,最终导致其控制学习记忆和调节情绪的功能衰退,直至形成抑郁。
Depression is an incapacitating disorder,primarily characterized by a lowering of mood and an inhibition of both mental and physical activities.The incidence of depression has increased year by year and with a younger trend.The illness often results in huge emotional and financial consequences.WHO predicts that by 2020 depression will become one of the 2 major diseases leading to human death and disability.For complex causes and polymorphism symptoms,its pathogenesis has not yet entirely clear.Current major hypothesis considers that stress enhance the HPA axis, cause monoamine neurotransmitter systems decline,finally lead to depression.But present antidepressants designed base on monoamine neurotransmitters doctrine exist many limitations,such as poor specification,drug interactions,side effects,and tolerance.Recent research has focused on a new kind of antidepressant drugs which directly act on the relevant receptors.Neuropeptide is a kind of peptide to deliver message,widely exist in the nervous system and various parts of the body,involved in the regulation of stress response,cardiovascular activities and so on.It significantly impacts neurotransmitter metabolism and function,is considered to monoamine neurotransmitter upstream regulatory factors,and its incidence in the course of depression is being strong concerned.
In this study,first we use forced swim,tail suspension,chronic unpredictable miled stress and olfactory bulbectomy to establish depression model of rats,Open-field behavior test was used to detect the locomotion activity,Sugar consumption was measured to observe the degree of happiness and reward.The method of Morris water Maze was used to assay the ability of learning and memory,and HPLC-UV was employed to analyze the level of blood serum corticosterone.The results showed that compared with the control group,the body weight,sugar consumption,locomotion activity,learning and short term memory ability for chronic stress and olfactory bulbectomy models decreased extremely,the level of serum corticosterone increased evidently,and no apparent difference in the long term memory.While,the body weight,sugar consumption,locomotion activity,learning and short term memory ability,level of serum corticosterone for forced swim and tail suspension models were not significantly changed.These results suggested that both chronic stress and olfactory bulbectomy could cause rats depression,were effective model building methods,but forced swim and tail suspension were not.
In second part of research work:The chronic unpredictable stress model of rats was adopted.The method of DNA microarray,RT-PCR and fluorescence quantitative PCR were used to test the expression of Neuropeptides and their receptors in hypothalamus, dorsal raphe nucleus and hippocampus.The results showed that the expression of CRF and its receptor1 in hypothalamus,dorsal raphe nucleus and hippocampus increased obviously.The expression of GAL and its receptor1,receptor2 increased except GAL receptor 1 in hypothalamus and hippocampus decreased.The expression of NPY and its receptor NPYR1,NPYR2 and NPYR5 increased.The expression of AVP and its receptor AVPR1a,AVPR1b increased except AVP in hippocampus didn't change.These results suggested that in the course of depression,CRF,GAL and NPY are likely involved in the regulation of neuronal function.
Our third part of research work aim to verify the function of CRF,GAL and NPY in depression.1.Chronic intra-cerebral ventricular administration of CRF in normal rats for 21 days were performed and compared with the depression model of chronic unpredictable miled stress(CUMS)in rats.2.Chronic intra-cerebral ventricular adininistration of GAL,GAL2-11(the specific receptor-2 agonist)and NPY respectively in CUMS model were performed and compared with intra-cerebral ventricular administration of aCSF in CUMS model.Open-field behavior test was used to detect the locomotion activity.The method of Morris water Maze was used to assay the ability of learning and memory.The results showed that,1.The rats with chronic administration of CRF consistently decreased the weight gain,locomotion activity and the ability of spatial learning and memory as the CUMS model.2.The CUMS model chronic intra-cerebral ventricular administration of GAL,GAL2-11 (the specific receptor-2 agonist)and NPY respectively increased the locomotion activity obviously.Meanwhile,GAL2-11 significantly improved the ability of learning for CUMS model.These results suggested that sustained elevation of CRF induced by stress may be the chief factor for depression.The higher expression for GAL,GAL receptor 2 and NPY in some brain area may be the protective response for depression.Through the CRF receptor R1,GAL receptor 2 and the NPY system to explore antidepressant drug targets,with broad prospects.
The fourth part of our study aim to explore the role of CRF and corticosterone in the hippocampus-related depression mechanism.1.The chronic unpredictable stress and olfactory bulbectomy model of rats were adopted.The results of LTP and LTD in hippocampus CA1 were recorded to observe the synaptic plasticity of hippocampus neurons.HPLC-FLU was employed to analyze the level of 5-HT and NE in hippocampus.2.Optical microscopy and transmission electron microscopy were used to observe the hippocampus cells structure for CUMS model,OB model and CRF icv rats.3.The method of primary hippocampal nerve cell culture was used to observe the effect of CRF and corticosterone.The results showed that,1.The synaptic plasticity of hippocampus neurons for two models decreased significantly,the level of 5-HT in hippocampus decreased evidently and Neurotransmitter disordered.2.The hippocampus cells structure for CUMS model,OB model and CRF icv rats were all seriously damaged,nuclear pyknosis or dissolved,cytoplasm and hollowing out of internal mitochondria,mitochondria swelled and reduced;synaptic reduced, postsynaptic membrane thicken.3.On hippocampal neurons,different concentrations of CRF did no significant impact;Low concentration(10~(-8)mol / L)of corticosterone had protective effect,when greater than 10~(-7)mol / L,reflected dose dependent injury. These results indicate that stress firstly infect hippocampus,cause the release of CRF, then Cortisol or corticosterone generate and directly damage the structure of hippocampal neurons,cell necrosis or apoptosis,which eventually led to hippocampus dysfunction and even depression.
Conclusions:
1.Both chronic stress and olfactory bulbectomy could cause rats depression,in a variety of evaluation have consistency,were effective model building means;
2.Sustained elevation of CRF induced by stress may be the chief factor for depression.The higher expression for GAL,GAL receptor 2 and NPY in some brain area may be the protective response.Through the CRF receptor R1,GAL receptor 2 and the NPY system to explore antidepressant drug targets,with broad prospects;
3.Stress caused hippocampus substantial damaged,which indicate that stress firstly infect hippocampus,cause the release of CRF,then Cortisol or corticosterone generate and directly damage the structure of hippocampal neurons,cell necrosis or apoptosis,which eventually led to hippocampus dysfunction and even depression.
本论文研究的第一部分工作:采用强迫游泳、悬尾、慢性未预知应激和嗅球切除手段分别建立抑郁症大鼠模型,运用旷场行为实验(open-field behavior)检测大鼠主动性活动能力,通过测量糖水消耗量观察大鼠幸福感和奖赏程度,用Morris水迷宫法检测大鼠空间学习记忆能力,HPLC-UV法测定大鼠血清皮质酮含量。结果显示,与对照组相比,慢性应激和嗅球切除两种建模方式均使大鼠的体重增量明显降低,糖水消耗量显著减少,主动性活动能力和空间探索欲望明显下降,血清皮质酮含量显著升高,空间学习和短时记忆能力明显降低,对大鼠空间记忆的长时保持能力的影响则不显著。而强迫游泳和悬尾两种建模方式对大鼠的体重增量、糖水消耗量、主动性活动能力和空间探索欲望、血清皮质酮含量以及空间学习和短时记忆能力的影响都不明显。以上结果表明,慢性应激和嗅球切除两种建模方式可使大鼠表现出明显的抑郁症特征,在多种评价指标上有着一致性,是较理想的建模手段;而单一的强迫游泳或悬尾可能使动物对同一种刺激产生适应,建模效果不佳。
研究的第二部分工作:采用慢性未预知应激建立抑郁症大鼠模型,运用基因芯片、RT-PCR和荧光定量PCR技术检测大鼠下丘脑、中缝背核和海马脑区神经肽及其受体的表达。结果显示,应激模型大鼠下丘脑、中缝背核、海马三个脑区的CRF及其受体R1 mRNA的表达量都明显增加。除了GALR1在下丘脑及海马表达减少外,GAL及其受体GALR1及GALR2在下丘脑、中缝背核、海马三个脑区的表达均显著增加。NPY及其受体NPYR1,NPYR2和NPYR5在三个脑区的表达都明显上升。除了AVP在海马脑区表达差异不显著外,AVP及其受体AVPR1a和AVPR1b在以上三个脑区的表达也都明显增加。以上结果表明,在抑郁症发生发展过程中,CRF、GAL和NPY很可能参与了神经元功能的调节。
第三部分的研究工作对CRF、GAL和NPY在抑郁症形成中的作用分别进行功能验证。1.正常大鼠侧脑室慢性注射CRF 21天并与慢性非预见性应激刺激21天建立的抑郁症模型大鼠进行比较。2.慢性应激模型大鼠侧脑室分别慢性注射GAL、GAL2-11(受体2的特异性激动剂)以及NPY与应激模型大鼠侧脑室注射aCSF进行比较。运用旷场行为实验(open-field behavior)观察大鼠主动性活动能力,采用Morris水迷宫法,以训练期的逃避潜伏期为指标检测大鼠空间学习记忆能力。结果显示,1.正常大鼠侧脑室慢性注射CRF 21天之后,其体重增量、主动性活动和学习记忆能力与慢性应激模型大鼠一样均明显下降。2.大鼠慢性应激建模成功后,侧脑室分别慢性注射GAL、GAL2-11以及NPY,其主动性活动能力均显著提高。未建模大鼠侧脑室慢性注射GAL,主动性活动没有显著的变化。另外,GAL2-11可使抑郁症大鼠的学习能力明显改善,GAL、NPY的效果则不明显。以上结果说明,慢性应激导致机体CRF分泌持续增加可能是抑郁症发病的直接原因。抑郁症形成过程中,GAL及其受体2(GALR2)的高表达,NPY系统的表达上调可能都是机体的保护性调节。通过CRF受体R1,GAL受体2以及NPY系统探寻抗抑郁药物靶点和开发新药,具有广阔前景。
研究的第四部分工作探讨CRF及皮质酮在海马相关的抑郁症发生机制中的作用。1.采用慢性应激和嗅球切除两种抑郁症模型大鼠,运用电生理方法,诱导并记录大鼠海马CA1区LTP与LTD场兴奋性突触后电位(f-EPSP),观察海马突触可塑性。用HPLC-FLU法检测大鼠海马脑区5-HT,NE两种神经递质含量。2.运用光学显微镜和透射电子显微镜技术观察慢性应激、嗅球切除和侧脑室慢性注射CRF对大鼠海马神经细胞结构的影响。3.通过离体培养的大鼠海马神经细胞,分别观察CRF和皮质酮对海马神经细胞的作用模式。结果显示,1.两种模型大鼠海马CA1区诱导LTP和LTD的能力明显低于相应对照组,海马突触可塑性均显著降低;海马脑区的5—HT含量明显减少,NE含量变化不大,单胺类神经递质含量出现紊乱。2.慢性应激、嗅球切除和侧脑室慢性注射CRF三种方式均能引起大鼠海马神经细胞结构严重损伤,细胞核固缩或溶解,细胞质及线粒体内部出现空洞化,线粒体肿胀、嵴断裂,数量减少;突触稀疏,突触后膜增厚。3.连续加药9天,不同浓度的CRF对离体海马神经细胞的存活率没有明显的影响。连续作用7天,与对照组比较,低浓度(10~(-8)mol/L)的皮质酮对海马神经细胞有一定的保护作用,当浓度大于一定数值(10~(-7)mol/L)时,则反映出浓度相关的损伤效应。以上结果提示,应激首先作用于海马,引起CRF释放,使大量糖皮质激素(GC)产生并释放,导致机体皮质醇(酮)含量增加,后者直接损伤海马神经细胞结构,细胞坏死或凋亡,海马容积变小,最终导致其控制学习记忆和调节情绪的功能衰退,直至形成抑郁。
结论:
1.慢性应激和嗅球切除两种建模方式可使大鼠表现出明显的抑郁症特征,在多种评价指标上有着一致性,是较理想的建模手段;
2.慢性应激导致机体CRF分泌持续增加可能是抑郁症发病的直接原因。抑郁症形成过程中,GAL及其受体2(GALR2)的高表达,NPY系统的表达上调都可能是机体的保护性调节。通过CRF受体R1,GAL受体2以及NPY系统探寻抗抑郁药物靶点和开发新药,具有广阔前景;
3.应激刺激引起海马脑区的实质性损伤,提示应激刺激首先引起机体下丘脑CRF的分泌和导致HPA轴功能亢进,导致糖皮质激素急剧升高,皮质醇(酮)含量增加。后者直接损伤海马神经细胞结构,细胞坏死或凋亡,海马容积变小,最终导致其控制学习记忆和调节情绪的功能衰退,直至形成抑郁。
Depression is an incapacitating disorder,primarily characterized by a lowering of mood and an inhibition of both mental and physical activities.The incidence of depression has increased year by year and with a younger trend.The illness often results in huge emotional and financial consequences.WHO predicts that by 2020 depression will become one of the 2 major diseases leading to human death and disability.For complex causes and polymorphism symptoms,its pathogenesis has not yet entirely clear.Current major hypothesis considers that stress enhance the HPA axis, cause monoamine neurotransmitter systems decline,finally lead to depression.But present antidepressants designed base on monoamine neurotransmitters doctrine exist many limitations,such as poor specification,drug interactions,side effects,and tolerance.Recent research has focused on a new kind of antidepressant drugs which directly act on the relevant receptors.Neuropeptide is a kind of peptide to deliver message,widely exist in the nervous system and various parts of the body,involved in the regulation of stress response,cardiovascular activities and so on.It significantly impacts neurotransmitter metabolism and function,is considered to monoamine neurotransmitter upstream regulatory factors,and its incidence in the course of depression is being strong concerned.
In this study,first we use forced swim,tail suspension,chronic unpredictable miled stress and olfactory bulbectomy to establish depression model of rats,Open-field behavior test was used to detect the locomotion activity,Sugar consumption was measured to observe the degree of happiness and reward.The method of Morris water Maze was used to assay the ability of learning and memory,and HPLC-UV was employed to analyze the level of blood serum corticosterone.The results showed that compared with the control group,the body weight,sugar consumption,locomotion activity,learning and short term memory ability for chronic stress and olfactory bulbectomy models decreased extremely,the level of serum corticosterone increased evidently,and no apparent difference in the long term memory.While,the body weight,sugar consumption,locomotion activity,learning and short term memory ability,level of serum corticosterone for forced swim and tail suspension models were not significantly changed.These results suggested that both chronic stress and olfactory bulbectomy could cause rats depression,were effective model building methods,but forced swim and tail suspension were not.
In second part of research work:The chronic unpredictable stress model of rats was adopted.The method of DNA microarray,RT-PCR and fluorescence quantitative PCR were used to test the expression of Neuropeptides and their receptors in hypothalamus, dorsal raphe nucleus and hippocampus.The results showed that the expression of CRF and its receptor1 in hypothalamus,dorsal raphe nucleus and hippocampus increased obviously.The expression of GAL and its receptor1,receptor2 increased except GAL receptor 1 in hypothalamus and hippocampus decreased.The expression of NPY and its receptor NPYR1,NPYR2 and NPYR5 increased.The expression of AVP and its receptor AVPR1a,AVPR1b increased except AVP in hippocampus didn't change.These results suggested that in the course of depression,CRF,GAL and NPY are likely involved in the regulation of neuronal function.
Our third part of research work aim to verify the function of CRF,GAL and NPY in depression.1.Chronic intra-cerebral ventricular administration of CRF in normal rats for 21 days were performed and compared with the depression model of chronic unpredictable miled stress(CUMS)in rats.2.Chronic intra-cerebral ventricular adininistration of GAL,GAL2-11(the specific receptor-2 agonist)and NPY respectively in CUMS model were performed and compared with intra-cerebral ventricular administration of aCSF in CUMS model.Open-field behavior test was used to detect the locomotion activity.The method of Morris water Maze was used to assay the ability of learning and memory.The results showed that,1.The rats with chronic administration of CRF consistently decreased the weight gain,locomotion activity and the ability of spatial learning and memory as the CUMS model.2.The CUMS model chronic intra-cerebral ventricular administration of GAL,GAL2-11 (the specific receptor-2 agonist)and NPY respectively increased the locomotion activity obviously.Meanwhile,GAL2-11 significantly improved the ability of learning for CUMS model.These results suggested that sustained elevation of CRF induced by stress may be the chief factor for depression.The higher expression for GAL,GAL receptor 2 and NPY in some brain area may be the protective response for depression.Through the CRF receptor R1,GAL receptor 2 and the NPY system to explore antidepressant drug targets,with broad prospects.
The fourth part of our study aim to explore the role of CRF and corticosterone in the hippocampus-related depression mechanism.1.The chronic unpredictable stress and olfactory bulbectomy model of rats were adopted.The results of LTP and LTD in hippocampus CA1 were recorded to observe the synaptic plasticity of hippocampus neurons.HPLC-FLU was employed to analyze the level of 5-HT and NE in hippocampus.2.Optical microscopy and transmission electron microscopy were used to observe the hippocampus cells structure for CUMS model,OB model and CRF icv rats.3.The method of primary hippocampal nerve cell culture was used to observe the effect of CRF and corticosterone.The results showed that,1.The synaptic plasticity of hippocampus neurons for two models decreased significantly,the level of 5-HT in hippocampus decreased evidently and Neurotransmitter disordered.2.The hippocampus cells structure for CUMS model,OB model and CRF icv rats were all seriously damaged,nuclear pyknosis or dissolved,cytoplasm and hollowing out of internal mitochondria,mitochondria swelled and reduced;synaptic reduced, postsynaptic membrane thicken.3.On hippocampal neurons,different concentrations of CRF did no significant impact;Low concentration(10~(-8)mol / L)of corticosterone had protective effect,when greater than 10~(-7)mol / L,reflected dose dependent injury. These results indicate that stress firstly infect hippocampus,cause the release of CRF, then Cortisol or corticosterone generate and directly damage the structure of hippocampal neurons,cell necrosis or apoptosis,which eventually led to hippocampus dysfunction and even depression.
Conclusions:
1.Both chronic stress and olfactory bulbectomy could cause rats depression,in a variety of evaluation have consistency,were effective model building means;
2.Sustained elevation of CRF induced by stress may be the chief factor for depression.The higher expression for GAL,GAL receptor 2 and NPY in some brain area may be the protective response.Through the CRF receptor R1,GAL receptor 2 and the NPY system to explore antidepressant drug targets,with broad prospects;
3.Stress caused hippocampus substantial damaged,which indicate that stress firstly infect hippocampus,cause the release of CRF,then Cortisol or corticosterone generate and directly damage the structure of hippocampal neurons,cell necrosis or apoptosis,which eventually led to hippocampus dysfunction and even depression.
引文
1.Willner,P.and P.J.Mitchell,The validity of animal models of predisposition to depression.Behav Pharmacol,2002.13(3):p.169-88.
2.Burn,D.J.,Beyond the iron mask:towards better recognition and treatment of depression associated with Parkinson's disease.Mov Disord,2002.17(3):p.445-54.
3.Overstreet,D.H.,et al.,The Flinders Sensitive Line rat:a selectively bred putative animal model of depression.Neurosci Biobehav Rev,2005.29(4-5):p.739-59.
4.Shenal,B.V.,D.W.Harrison,and H.A.Demaree,The neuropsychology of depression:a literature review and preliminary model.Neuropsychol Rev,2003.13(1):p.33-42.
5.Schildkraut,J.J.,The catecholamine hypothesis of affective disorders:a review of supporting evidence.Am J Psychiatry,1965.122(5):p.509-22.
6.Bunney,W.E.,Jr.and J.M.Davis,Norepinephrine in depressive reactions.A review.Arch Gen Psychiatry,1965.13(6):p.483-94.
7.Delgado,P.L.,Depression:the case for a monoamine deficiency.J Clin Psychiatry,2000.61Suppl 6:p.7-ll.
8.Elhwuegi,A.S.,Central monoamines and their role in major depression.Prog Neuropsychopharmacol Biol Psychiatry,2004.28(3):p.435-51.
9.Nutt,D.J.,The neuropharmacology of serotonin and noradrenaline in depression.Int Clin Psychopharmacol,2002.17 Suppl 1:p.S1-12.
10.Meisch,J.J.,[Monoamines and mental depression].Bull Soc Sci Med Grand Duche Luxemb,1971.108(1):p.35-46.
11.Gold,P.W.and G.P.Chrousos,Organization of the stress system and its dysregulation in melancholic and atypical depression:high vs low CRH/NE states.Mol Psychiatry,2002.7(3):p.254-75.
12.Nishizaki,T.,et al.,Short-term depression and long-term enhancement of ACh-gated channel currents induced by linoleic and linolenic acid.Brain Res,1997.751(2):p.253-8.
13.Rodrigues,P.S.,et al.,Involvement of GABA and ACh in retinal spreading depression:effects of "low calcium-high magnesium" solutions.Exp Brain Res,1988.73(3):p.659-64.
14.Gotlib,I.H.,et al.,HP A axis reactivity:a mechanism underlying the associations among 5-HTTLPR,stress,and depression.Biol Psychiatry,2008.63(9):p.847-51.
15.Ma,L.,B.Hu,and A.L.Kenter,Ig S gamma-specific DNA binding protein SNAP is related to the helix-loop-helix transcription factor E47.Int Immunol,1997.9(7):p.1021-9.
16.Heuser,I.,The HPA-system in late-life depression.Aging(Milano),1997.9(4 Suppl):p.40-1.
17.Mokrani,M.C.,et al.,HPA axis dysfunction in depression:correlation with monoamine system abnormalities.Psychoneuroendocrinology,1997.22 Suppl 1:p.S63-8.
18.Lotufo-Neto,F.,M.Trivedi,and M.E.Thase,Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression.Neuropsychopharmacology,1999.20(3):p.226-47.
19.Wong,M.L.and J.Licinio,From monoamines to genomic targets:a paradigm shift for drug discovery in depression.Nat Rev Drug Discov,2004.3(2):p.136-51.
20.Thakker-Varia,S.and J.Alder,Neuropeptides in depression:role of VGF.Behav Brain Res,2009.197(2):p.262-78.
21.Landgraf,R.,Neuropeptides in anxiety and depression.Amino Acids,2006.31(3):p.211-3.
22.Holmes,A.,et al.,Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders.Trends Pharmacol Sci,2003.24(11):p.580-8.
23.Willner,P.,Validity,reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation.Psychopharmacology(Berl),1997.134(4):p.319-29.
24.Overstreet,D.H.,The Flinders sensitive line rats:a genetic animal model of depression.Neurosci Biobehav Rev,1993.17(1):p.51-68.
25.Katz,R.J.,K.A.Roth,and BJ.Carroll,Acute and chronic stress effects on open field activity in the rat:implications for a model of depression.Neurosci Biobehav Rev,1981.5(2):p.247-51.
26.Slotkin,T.A.,F.J.Seidler,and J.C.Ritchie,Regional differences in brain monoamine oxidase subtypes in an animal model of geriatric depression:effects of olfactory bulbectomy in young versus aged rats.Brain Res,2000.882(1-2):p.149-54.
27.Wrynn,A.S.,et al.,An in-vivo magnetic resonance imaging study of the olfactory bulbectomized rat model of depression.Brain Res,2000.879(1-2):p.193-9.
28.Van Hoomissen,J.D.,et al.,Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat.Brain Res,2003.974(1-2):p.228-35.
29.Sarkaki,A.,et al.,Effect of ovariectomy on reference memory version of Morris water maze in young adult rats.Iran Biomed J,2008.12(2):p.123-8.
30.Frazer,A.and D.A.Morilak,What should animal models of depression model? Neurosci Biobehav Rev,2005.29(4-5):p.515-23.
31.Yadid,G.,et al.,Elucidation of the neurobiology of depression:insights from a novel genetic animal model Prog Neurobiol,2000.62(4):p.353-78.
32.Pottinger,T.G.,The effect of stress and exogenous Cortisol on receptor-like binding of Cortisol in the liver of rainbow trout,Oncorhynchus mykiss.Gen Comp Endocrinol,1990.78(2):p.194-203.
33.Kelly,J.P.,A.S.Wrynn,and B.E.Leonard,The olfactory bulbectomized rat as a model of depression:an update.Pharmacol Ther,1997.74(3):p.299-316.
34.Keller,P.A.,et al,The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments.Arch Pharm(Weinheim),2006.339(7):p.346-55.
35.Nakazawa,K.,et al.,Requirement for hippocampal CAS NMDA receptors in associative memory recall.Science,2002.297(5579):p.211-8.
36.Pfaffl,M.W.,A new mathematical model for relative quantification in real-time RT-PCR.Nucleic Acids Res,2001.29(9):p.e45.
37.Chaki,S.and S,Okuyama,[Neuropeptide receptors:novel therapeutic targets for depression].Nippon Yakurigaku Zasshi,2006.127(3):p.196-200.
38.Song,C.,B.Earley,and B.E.Leonard,The effects of central administration of neuropeptide Y on behavior,neurotransmitter,and immune functions in the olfactory bulbectomized rat model of depression.Brain Behav Immun,1996.10(1):p.1-16.
39.Liu,J.P.,et al.,Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophysial-portal circulation of the conscious sheep.Ⅱ.The central noradrenergic and neuropeptide Y pathways cause immediate and prolonged hypothalamic-pituitary-adrenal activation.Potential involvement in the pseudo-Cwhing's syndrome of endogenous depression and anorexia nervosa.J Clin Invest,1994.93(4):p.1439-50.
40.Finta,E.P.,J.T.Regenold,and P.Illes,Depression by neuropeptide Y of noradrenergic inhibitory postsynaptic potentials of locus coeruleus neurones.Naunyn Schmiedebergs Arch Pharmacol,1992.346(4):p.472-4.
41.Barbaccia,M.L.,et al.,Diazepam-binding inhibitor.A brain neuropeptide present in human spinal fluid:studies in depression,schizophrenia,and Alzheimer's disease.Arch Gen Psychiatry,1986.43(12):p.1143-7.
42.Koob,G.F.,Corticotropin-releasing factor,norepinephrine,and stress.Biol Psychiatry,1999.46(9):p.1167-80.
43.Nemeroff,C.B.,The corticotropin-releasing factor(CRF) hypothesis of depression:new findings and new directions.Mol Psychiatry,1996.1(4):p.336-42.
44.Duggan,A.W.and R.C.Riley,Studies of the release of immunoreactive galanin and dynorphin A(1-8) in the spinal cord of the rat.Prog Brain Res,1996.110:p.137-47.
45.Mazarati,A.M.,et al,Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus.J Neurosci,1998.18(23):p.10070-7.
46.Branchek,T.A.,et al.,Galanin receptor subtypes.Trends Pharmacol Sci,2000.21(3):p.109-17.
47.Halliwell,B.and J.M.Gutteridge,Role of free radicals and catalytic metal ions in human disease:an overview.Methods Enzymol,1990.186:p.1-85.
48.Eaton,K.,F.R.Sallee,and R.Sah,Relevance of neuropeptide Y(NPY) in psychiatry.Curr Top Med Chem,2007.7(17):p.1645-59.
49.Redrobe,J.P.,Y.Dumont,and R.Quirion,Neuropeptide Y(NPY) and depression:from animal studies to the human condition.Life Sci,2002.71(25):p.2921-37.
50.Jimenez Vasquez,P.A.,et al.,Neuropeptide Y in brains of the Flinders Sensitive Line rat,a model of depression.Effects of electroconvulsive stimuli and d-amphetamine on peptide concentrations and locomotion.Behav Brain Res,2000.111(1-2):p.115-23.
51.Heilig,M.,The NPY system in stress,anxiety and depression.Neuropeptides,2004.38(4):p.213-24.
52.Saito,S.,et al.,ICV CRF and isolation stress differentially enhance plasma corticosterone concentrations in layer-and meat-type neonatal chicks.Comp Biochem Physiol A Mol Integr Physiol,2005.141(3):p.305-9.
53.Clifford,P.S.,et al.,Effects of ICV administration of the alphalA-adrenoceptor antagonist 5-methylurapidil on concurrent measures of eating and locomotion after cocaine in the rat.Life Sci,2007.81(13):p.1059-65.
54.Hedlund,P.B.and K.Fuxe,Galanin and 5-HTIA receptor interactions as an integrative mechanism in 5-HT neurotransmission in the brain.Ann N Y Acad Sci,1996.780:p.193-212.
55.Langel,U.,et al.,A galanin-mastoparan chimeric peptide activates the Na+,K(+)-ATPase and reverses its inhibition by ouabain.Regul Pept,1996.62(1):p.47-52.
56.Rich,E.L.and L.M.Romero,Exposure to chronic stress downregulates corticosterone responses to acute stressors.Am J Physiol Regul Integr Comp Physiol,2005.288(6):p.R1628-36.
57.Csiszar,A.,et al.,Oxidative stress and accelerated vascular aging:implications for cigarette smoking.Front Biosci,2009.14:p.3128-44.
58.Anzalone,R.,et al.,Role of endothelial cell stress in the pathogenesis of chronic heart failure.Front Biosci,2009.14:p.2238-47.
59.Simmons,D.A.and P.A.Broderick,Cytokines,stressors,and clinical depression:augmented adaptation responses underlie depression pathogenesis.Prog Neuropsychopharmacol Biol Psychiatry,2005.29(5):p.793-807.
60.Alonso,R.,et al,Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.Mol Psychiatry,2004.9(3):p.278-86,224.
61.Swiergiel,A.H.,I.L.Leskov,and A.J.Dunn,Effects of chronic and acute stressors and CRF on depression-like behavior in mice.Behav Brain Res,2008.186(1):p.32-40.
62.Valdez,G.R.,Development of CRF1 receptor antagonists as antidepressants and anxiolytics:progress to date.CNS Drugs,2006.20(11):p.887-96.
63.Kehne,J.H.,The CRF1 receptor,a novel target for the treatment of depression,anxiety,and stress-related disorders.CNS Neurol Disord Drug Targets,2007.6(3):p.163-82.
64.Hauger,R.L.,et al.,Corticotropin releasing factor(CRF) receptor signaling in the central nervous system:new molecular targets.CNS Neurol Disord Drag Targets,2006.5(4):p.453-79.
65.Chen,C.,Recent advances in small molecule antagonists of the corticotropin-releasing factor type-1 receptor-focus on pharmacology and pharmacokinetics.Curr Med Chem,2006.13(11):p.1261-82.
66.Tatemoto,K.,et al.,Galanin-a novel biologically active peptide from porcine intestine.FEBS Lett,1983.164(1):p.124-8.
67.Finn,P.D.,D.K.Clifton,and R.A.Steiner,The regulation of galanin gene expression in gonadotropin-releasing hormone neurons.Mol Cell Endocrinol,1998.140(1-2):p.137-42.
68.Crawley,J.N.,The role of galanin in feeding behavior.Neuropeptides,1999.33(5):p.369-75.
69.Miller,M.A.,Regulation of galanin in memory pathways.Ann N Y Acad Sci,1998.863:p.323-41.
70.Sauer-Ramirez,J.L.,L.M.Ballesteros,and O.Hernandez-Perez,[Galanin,a new neuropeptide.Review].Ginecol Obstet Mex,1996.64:p.325-31.
71.Leibowitz,S.F.,Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight.Ann N Y Acad Sci,1998.863:p.206-20.
72.Groneberg,D.A.,et al.,Neuropeptide Y(NPY).Pulm Pharmacol Ther,2004.17(4):p.173-80.
73.Tatemoto,K.,Neuropeptide Y:complete amino acid sequence of the brain peptide.Proc Natl Acad Sci U S A,1982.79(18):p.5485-9.
74.Allen,Y.S.,et al.,Neuropeptide Y distribution in the rat brain.Science,1983.221(4613):p.877-9.
75.Edvinsson,L.,et al.,Neuropeptide Y:cerebrovascular innervation and vasomotor effects in the cat.Neurosci Lett,1983.43(1):p.79-84.
76.Pesonen,U.,Human NPY gene variants in cardiovascular and metabolic diseases.EXS,2006(95):p.247-67.
77.Pelz,K.M.and J.Dark,ICV NPY Y1 receptor agonist but not Y5 agonist induces torpor-like hypothermia in cold-acclimated Siberian hamsters.Am J Physiol Regul Integr Comp Physiol,2007.292(6):p.R2299-311.
78.Chan,Y.Y.,D.K.Clifton,and R.A.Steiner,Role of NPY neurones in GH-dependent feedback signalling to the brain.Horm Res,1996.45 Suppl 1:p.12-4.
79.Sajdyk,T.J.,A.Shekhar,and D.R.Gehlert,Interactions between NPY and CRF in the amygdala to regulate emotionality.Neuropeptides,2004.38(4):p.225-34.
80.Tucker,G.J.,Neurological disorders and depression.Semin Clin Neuropsychiatry,2002.7(3):p.213-20.
81.Zhao,Z.,et al.,Hippocampus shape analysis and late-life depression.PLoS ONE,2008.3(3):p.e1837.
82.Sheline,Y.I.,B.L.Mittler,and M.A.Mintun,The hippocampus and depression.Eur Psychiatry,2002.17 Suppl 3:p.300-5.
83.Mervaala,E.,et al.,Quantitative MRI of the hippocampus and amygdala in severe depression.Psychol Med,2000.30(1):p.117-25.
84.Yi,P.L.,et al.,The involvement of metabotropic glutamate receptors in long-term depression of N-methyl-D-aspartate receptor-mediated synaptic potential in the rat hippocampus.Neurosci Lett,1995.185(3):p.207-10.
85.Walf,A.A.and C.A.Frye,A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior.Neuropsychopharmacology,2006.31(6):p.1097-111.
86.Davis,S.,S.P.Butcher,and R.G.Morris,The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate(D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro.J Neurosci,1992.12(1):p.21-34.
87.Katsube,T.,et al.,Changes of nutritional status after distal gastrectomy in patients with gastric cancer.Hepatogastroenterology,2008.55(86-87):p.1864-7.
88.Feng,Z.,et al.,Synthesis and activity in enhancing long-term potentiation(LTP) of clausenamide stereoisomers.Bioorg Med Chem Lett,2009.19(8):p.2112-5.
89.Dubrovsky,B.,A.Tatarinov-Levin,and J.Harris,Effects of the active neurosteroid allotetrahydrodeoxycorticosterone on long-term potentiation in the rat hippocampus:implications for depression.Prog Neuropsychopharmacol Biol Psychiatry,2004.28(6):p.1029-34.
90.Sasaki,T.,et al.,Reverse Optical Trawling for Synaptic Connections in Situ.J Neurophysiol,2009.
91.Youn,D.H.,et al.,Altered long-term synaptic plasticity and kainate-induced Ca2+transients in the substantia gelatinosa neurons in GLU(K6)-deficient mice.Brain Res Mol Brain Res,2005.142(1):p.9-18.
92.Thomas,L.,et al.,GENetic and clinical Predictors Of treatment response in Depression:the GenPod randomised trial protocol.Trials,2008.9:p.29.
93.Flint,J.,et al.,Genetic variants in major depression.Novartis Found Symp,2008.289:p.23-32;discussion 33-42,87-93.
94.Wasserman,D.,et al.,Depression in suicidal males:genetic risk variants in the CRHR1 gene.Genes Brain Behav,2009.8(1):p.72-9.
95.Power,A.C.and P.J.Cowen,Neuroendocrine challenge tests:assessment of 5-HT function in anxiety and depression.Mol Aspects Med,1992.13(3):p.205-20.
96.Sulser,F.,et al.,Regulation of recognition and action function of the norepinephrine(NE) receptor-coupled adenylate cyclase system in brain:implications for the therapy of depression.Neuropharmacology,1983.22(3 Spec No):p.425-31.
97.Yatham,L.N.,et al.,Hypothermic,ACTH,and Cortisol responses to ipsapirone in patients with mania and healthy controls.J Affect Disord,1999.54(3):p.295-301.
98.Whale,R,et al.,Decreased sensitivity of 5-HT(1D) receptors in melancholic depression.Br J Psychiatry,2001.178:p.454-7.
99.Pinchot,S.N.,R.Sippel,and H.Chen,ACTH-producing carcinoma of the pituitary with refractory Cushing's Disease and hepatic metastases:a case report and review of the literature.World J Surg Oncol,2009.7(1):p.39.
100.Ogren,S.O.,et al.,Alaproclate,a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia.J Neural Transm,1984.59(4):p.265-88.
101.Baicy,K.,et al.,Common substrates of dysphoria in stimulant drug abuse and primary depression:therapeutic targets.Int Rev Neurobiol,2005.65:p.117-45.
102.Janowsky,D.S.,et al.,A cholinomimetic model of motion sickness and space adaptation syndrome.Aviat Space Environ Med,1984.55(8):p.692-6.
103.Maj,M.,et al.,Agitated "unipolar" major depression:prevalence,phenomenology,and outcome.J Clin Psychiatry,2006.67(5):p.712-9.
104.Ossowska,K.,et al.,An influence of ligands of metabotropic glutamate receptor subtypes on parkinsonian-like symptoms and the striatopallidal pathway in rats.Amino Acids,2007.32(2):p.179-88.
105.Wrobel,A.,et al,Effect of chronic treatment with dexamethasone on brain dopamine receptors in mice.Pol J Pharmacol,2004.56(4):p.399-405.
106.Wardas,J.,et al.,The role of metabotropic glutamate receptors in regulation of striatal proenkephalin expression:implications for the therapy of Parkinson's disease.Neuroscience,2003.122(3):p.747-56.
107.Ossowska,K.,Neuronal basis of neuroleptic-induced extrapyramidal side effects.Pol J Pharmacol,2002.54(4):p.299-312.
108.Kleeberg,J.,et al.,ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase Cpathway in vivo.Am J Physiol Heart Circ Physiol,2004.286(4):p.H1339-46.
109.Swiecicki,L.,[Efficacy of citalopram in more than maximal dose in drug resistant depression.Case report].Psychiatr Pol,2003.37(5):p.839-44.
110.Pirkis,J.E.,Borderline personality disorder,drug use disorder,and worsening depression or substance abuse are significant predictors of suicide attempts in people with Axis Ⅰ and Ⅱdisorders.Evid Based Ment Health,2004.7(1):p.25.
111.Shelton,R.C.,et al.,Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A.Neuroscience,2009.158(4):p.1406-15.
112.Stein,M.D.,et al.,Pharmacotherapy plus psychotherapy for treatment of depression in active injection drug users.Arch Gen Psychiatry,2004.61(2):p.152-9.
113.Levy,S.E.,Microarray analysis in drug discovery:an uplifting view of depression.Sci STTCE,2003.2003(206):p.pe46.
114.Sandstrom,L.and E.E.Johansson,[Depression-a gender-disease in drug advertisement].Lakartidningen,2004.101(7):p.582-5.
115.Suljic,E.,et al.,[Comorbid depression in patients with epilepsy treated with single and multiple drug therapy].Med Arh,2003.57(5-6 Suppl 1):p.45-6.
116.Lambas-Senas,L.,et al.,Functional correlates for 5-HT(1A) receptors in maternally deprived rats displaying anxiety and depression-like behaviors.Prog Neuropsychopharmacol Biol Psychiatry,2009.33(2):p.262-8.
117.Vale,W.,et al.,Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.Science,1981.213(4514):p.1394-7.
118.Vella,E.J.and B.H.Friedman,Hostility and Anger In:Cardiovascular Reactivity and Recovery to Mental Arithmetic Stress.Int J Psychophysiol,2009.
119.Mitchell,A.J.,Depression as a risk factor for later dementia:a robust relationship? Age Ageing,2005.34(3):p.207-9.
120.Yalow,R.S.and S.A.Berson,Size heterogeneity of immunoreactive human ACTH in plasma and in extracts of pituitary glands and ACTH-producing thymoma.Biochem Biophys Res Commun,1971.44(2):p.439-45.
121.Marcus,S.M.,et al.,Gender differences in depression:findings from the STAR*D study.J Affect Disord,2005.87(2-3):p.141-50.
122.Young,A.M.and C.Boyd,Sexual Trauma,Substance Abuse,and Treatment Success in a Sample of African American Women Who Smoke Crack Cocaine.Subst Abus,2000.21(1):p.9-19.
123.Lundberg,J.M.,et al.,Neuropeptide Y(NPY)-like immunoreactfvity in peripheral noradrenergic neurons and effects of NPY on sympathetic function.Acta Physiol Scand,1982.116(4):p.477-80.
124.Allen,J.M.,et al.,Two novel related peptides,neuropeptide Y(NPY) and peptide YY(PYY)inhibit the contraction of the electrically stimulated mouse vas deferens.Neuropeptides,1982.3(2):p.71-7.
125.Chesher,T.and M.Young,Developing innovative strategies for multicultural communication.N S W Public Health Bull,2000.11(11):p.178-180.
126.Caberlotto,L.,et al.,Corticotropin-releasing hormone(CRH) mRNA expression in rat central amygdala in cannabinoid tolerance and withdrawal:evidence for an allostatic shift?Neuropsychopharmacology,2004.29(1):p.15-22.
127.Sandi,C.,et al.,Chronic stress-induced alterations in amygdala responsiveness and behavior-modulation by trait anxiety and corticotropin-releasing factor systems.Eur J Neurosci,2008.28(9):p.1836-48.
128.Shen,P.J.,J.A.Larm,and A.L.Gundlach,Expression and plasticity of galanin systems in cortical neurons,oligodendrocyte progenitors and proliferative zones in normal brain and after spreading depression.Eur J Neurosci,2003.18(6):p.1362-76.
129.Kuteeva,E.,et al.,Galanin,galanin receptor subtypes and depression-like behaviour.Cell Mol Life Sci,2008.65(12):p.1854-63.
130.Kask,K.,M.Berthold,and T.Bartfai,Galanin receptors:involvement in feeding,pain,depression and Alzheimer's disease.Life Sci,1997.60(18):p.1523-33.
131.Kuteeva,E.,et al.,Differential role of galanin receptors in the regulation of depression-like behavior and mono amine/stress-related genes at the cell body level.Neuropsychopharmacology,2008.33(11):p.2573-85.
132.Holmes,A.,et al.,Phenotypic assessment ofgalanin over expressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior.Psychopharmacology(Berl),2005.178(2-3):p.276-85.
133.Chinet,L.,et al.,Substance use and depression.Comparative course in adolescents.Eur Child Adolesc Psychiatry,2006.15(3):p.149-55.
134.Evren,C.,S.Kural,and M.Erkiran,Antisocial personality disorder in Turkish substance dependent patients and its relationship with anxiety,depression and a history of childhood abuse.Isr J Psychiatry Relat Sci,2006.43(1):p.40-6.
135.Rotheram-Borus,M.J.,et al.,Substance use and its relationship to depression,anxiety,and isolation among youth living with HIV.Int J Behav Med,1999.6(4):p.293-311.
2.Burn,D.J.,Beyond the iron mask:towards better recognition and treatment of depression associated with Parkinson's disease.Mov Disord,2002.17(3):p.445-54.
3.Overstreet,D.H.,et al.,The Flinders Sensitive Line rat:a selectively bred putative animal model of depression.Neurosci Biobehav Rev,2005.29(4-5):p.739-59.
4.Shenal,B.V.,D.W.Harrison,and H.A.Demaree,The neuropsychology of depression:a literature review and preliminary model.Neuropsychol Rev,2003.13(1):p.33-42.
5.Schildkraut,J.J.,The catecholamine hypothesis of affective disorders:a review of supporting evidence.Am J Psychiatry,1965.122(5):p.509-22.
6.Bunney,W.E.,Jr.and J.M.Davis,Norepinephrine in depressive reactions.A review.Arch Gen Psychiatry,1965.13(6):p.483-94.
7.Delgado,P.L.,Depression:the case for a monoamine deficiency.J Clin Psychiatry,2000.61Suppl 6:p.7-ll.
8.Elhwuegi,A.S.,Central monoamines and their role in major depression.Prog Neuropsychopharmacol Biol Psychiatry,2004.28(3):p.435-51.
9.Nutt,D.J.,The neuropharmacology of serotonin and noradrenaline in depression.Int Clin Psychopharmacol,2002.17 Suppl 1:p.S1-12.
10.Meisch,J.J.,[Monoamines and mental depression].Bull Soc Sci Med Grand Duche Luxemb,1971.108(1):p.35-46.
11.Gold,P.W.and G.P.Chrousos,Organization of the stress system and its dysregulation in melancholic and atypical depression:high vs low CRH/NE states.Mol Psychiatry,2002.7(3):p.254-75.
12.Nishizaki,T.,et al.,Short-term depression and long-term enhancement of ACh-gated channel currents induced by linoleic and linolenic acid.Brain Res,1997.751(2):p.253-8.
13.Rodrigues,P.S.,et al.,Involvement of GABA and ACh in retinal spreading depression:effects of "low calcium-high magnesium" solutions.Exp Brain Res,1988.73(3):p.659-64.
14.Gotlib,I.H.,et al.,HP A axis reactivity:a mechanism underlying the associations among 5-HTTLPR,stress,and depression.Biol Psychiatry,2008.63(9):p.847-51.
15.Ma,L.,B.Hu,and A.L.Kenter,Ig S gamma-specific DNA binding protein SNAP is related to the helix-loop-helix transcription factor E47.Int Immunol,1997.9(7):p.1021-9.
16.Heuser,I.,The HPA-system in late-life depression.Aging(Milano),1997.9(4 Suppl):p.40-1.
17.Mokrani,M.C.,et al.,HPA axis dysfunction in depression:correlation with monoamine system abnormalities.Psychoneuroendocrinology,1997.22 Suppl 1:p.S63-8.
18.Lotufo-Neto,F.,M.Trivedi,and M.E.Thase,Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression.Neuropsychopharmacology,1999.20(3):p.226-47.
19.Wong,M.L.and J.Licinio,From monoamines to genomic targets:a paradigm shift for drug discovery in depression.Nat Rev Drug Discov,2004.3(2):p.136-51.
20.Thakker-Varia,S.and J.Alder,Neuropeptides in depression:role of VGF.Behav Brain Res,2009.197(2):p.262-78.
21.Landgraf,R.,Neuropeptides in anxiety and depression.Amino Acids,2006.31(3):p.211-3.
22.Holmes,A.,et al.,Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders.Trends Pharmacol Sci,2003.24(11):p.580-8.
23.Willner,P.,Validity,reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation.Psychopharmacology(Berl),1997.134(4):p.319-29.
24.Overstreet,D.H.,The Flinders sensitive line rats:a genetic animal model of depression.Neurosci Biobehav Rev,1993.17(1):p.51-68.
25.Katz,R.J.,K.A.Roth,and BJ.Carroll,Acute and chronic stress effects on open field activity in the rat:implications for a model of depression.Neurosci Biobehav Rev,1981.5(2):p.247-51.
26.Slotkin,T.A.,F.J.Seidler,and J.C.Ritchie,Regional differences in brain monoamine oxidase subtypes in an animal model of geriatric depression:effects of olfactory bulbectomy in young versus aged rats.Brain Res,2000.882(1-2):p.149-54.
27.Wrynn,A.S.,et al.,An in-vivo magnetic resonance imaging study of the olfactory bulbectomized rat model of depression.Brain Res,2000.879(1-2):p.193-9.
28.Van Hoomissen,J.D.,et al.,Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat.Brain Res,2003.974(1-2):p.228-35.
29.Sarkaki,A.,et al.,Effect of ovariectomy on reference memory version of Morris water maze in young adult rats.Iran Biomed J,2008.12(2):p.123-8.
30.Frazer,A.and D.A.Morilak,What should animal models of depression model? Neurosci Biobehav Rev,2005.29(4-5):p.515-23.
31.Yadid,G.,et al.,Elucidation of the neurobiology of depression:insights from a novel genetic animal model Prog Neurobiol,2000.62(4):p.353-78.
32.Pottinger,T.G.,The effect of stress and exogenous Cortisol on receptor-like binding of Cortisol in the liver of rainbow trout,Oncorhynchus mykiss.Gen Comp Endocrinol,1990.78(2):p.194-203.
33.Kelly,J.P.,A.S.Wrynn,and B.E.Leonard,The olfactory bulbectomized rat as a model of depression:an update.Pharmacol Ther,1997.74(3):p.299-316.
34.Keller,P.A.,et al,The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments.Arch Pharm(Weinheim),2006.339(7):p.346-55.
35.Nakazawa,K.,et al.,Requirement for hippocampal CAS NMDA receptors in associative memory recall.Science,2002.297(5579):p.211-8.
36.Pfaffl,M.W.,A new mathematical model for relative quantification in real-time RT-PCR.Nucleic Acids Res,2001.29(9):p.e45.
37.Chaki,S.and S,Okuyama,[Neuropeptide receptors:novel therapeutic targets for depression].Nippon Yakurigaku Zasshi,2006.127(3):p.196-200.
38.Song,C.,B.Earley,and B.E.Leonard,The effects of central administration of neuropeptide Y on behavior,neurotransmitter,and immune functions in the olfactory bulbectomized rat model of depression.Brain Behav Immun,1996.10(1):p.1-16.
39.Liu,J.P.,et al.,Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophysial-portal circulation of the conscious sheep.Ⅱ.The central noradrenergic and neuropeptide Y pathways cause immediate and prolonged hypothalamic-pituitary-adrenal activation.Potential involvement in the pseudo-Cwhing's syndrome of endogenous depression and anorexia nervosa.J Clin Invest,1994.93(4):p.1439-50.
40.Finta,E.P.,J.T.Regenold,and P.Illes,Depression by neuropeptide Y of noradrenergic inhibitory postsynaptic potentials of locus coeruleus neurones.Naunyn Schmiedebergs Arch Pharmacol,1992.346(4):p.472-4.
41.Barbaccia,M.L.,et al.,Diazepam-binding inhibitor.A brain neuropeptide present in human spinal fluid:studies in depression,schizophrenia,and Alzheimer's disease.Arch Gen Psychiatry,1986.43(12):p.1143-7.
42.Koob,G.F.,Corticotropin-releasing factor,norepinephrine,and stress.Biol Psychiatry,1999.46(9):p.1167-80.
43.Nemeroff,C.B.,The corticotropin-releasing factor(CRF) hypothesis of depression:new findings and new directions.Mol Psychiatry,1996.1(4):p.336-42.
44.Duggan,A.W.and R.C.Riley,Studies of the release of immunoreactive galanin and dynorphin A(1-8) in the spinal cord of the rat.Prog Brain Res,1996.110:p.137-47.
45.Mazarati,A.M.,et al,Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus.J Neurosci,1998.18(23):p.10070-7.
46.Branchek,T.A.,et al.,Galanin receptor subtypes.Trends Pharmacol Sci,2000.21(3):p.109-17.
47.Halliwell,B.and J.M.Gutteridge,Role of free radicals and catalytic metal ions in human disease:an overview.Methods Enzymol,1990.186:p.1-85.
48.Eaton,K.,F.R.Sallee,and R.Sah,Relevance of neuropeptide Y(NPY) in psychiatry.Curr Top Med Chem,2007.7(17):p.1645-59.
49.Redrobe,J.P.,Y.Dumont,and R.Quirion,Neuropeptide Y(NPY) and depression:from animal studies to the human condition.Life Sci,2002.71(25):p.2921-37.
50.Jimenez Vasquez,P.A.,et al.,Neuropeptide Y in brains of the Flinders Sensitive Line rat,a model of depression.Effects of electroconvulsive stimuli and d-amphetamine on peptide concentrations and locomotion.Behav Brain Res,2000.111(1-2):p.115-23.
51.Heilig,M.,The NPY system in stress,anxiety and depression.Neuropeptides,2004.38(4):p.213-24.
52.Saito,S.,et al.,ICV CRF and isolation stress differentially enhance plasma corticosterone concentrations in layer-and meat-type neonatal chicks.Comp Biochem Physiol A Mol Integr Physiol,2005.141(3):p.305-9.
53.Clifford,P.S.,et al.,Effects of ICV administration of the alphalA-adrenoceptor antagonist 5-methylurapidil on concurrent measures of eating and locomotion after cocaine in the rat.Life Sci,2007.81(13):p.1059-65.
54.Hedlund,P.B.and K.Fuxe,Galanin and 5-HTIA receptor interactions as an integrative mechanism in 5-HT neurotransmission in the brain.Ann N Y Acad Sci,1996.780:p.193-212.
55.Langel,U.,et al.,A galanin-mastoparan chimeric peptide activates the Na+,K(+)-ATPase and reverses its inhibition by ouabain.Regul Pept,1996.62(1):p.47-52.
56.Rich,E.L.and L.M.Romero,Exposure to chronic stress downregulates corticosterone responses to acute stressors.Am J Physiol Regul Integr Comp Physiol,2005.288(6):p.R1628-36.
57.Csiszar,A.,et al.,Oxidative stress and accelerated vascular aging:implications for cigarette smoking.Front Biosci,2009.14:p.3128-44.
58.Anzalone,R.,et al.,Role of endothelial cell stress in the pathogenesis of chronic heart failure.Front Biosci,2009.14:p.2238-47.
59.Simmons,D.A.and P.A.Broderick,Cytokines,stressors,and clinical depression:augmented adaptation responses underlie depression pathogenesis.Prog Neuropsychopharmacol Biol Psychiatry,2005.29(5):p.793-807.
60.Alonso,R.,et al,Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.Mol Psychiatry,2004.9(3):p.278-86,224.
61.Swiergiel,A.H.,I.L.Leskov,and A.J.Dunn,Effects of chronic and acute stressors and CRF on depression-like behavior in mice.Behav Brain Res,2008.186(1):p.32-40.
62.Valdez,G.R.,Development of CRF1 receptor antagonists as antidepressants and anxiolytics:progress to date.CNS Drugs,2006.20(11):p.887-96.
63.Kehne,J.H.,The CRF1 receptor,a novel target for the treatment of depression,anxiety,and stress-related disorders.CNS Neurol Disord Drug Targets,2007.6(3):p.163-82.
64.Hauger,R.L.,et al.,Corticotropin releasing factor(CRF) receptor signaling in the central nervous system:new molecular targets.CNS Neurol Disord Drag Targets,2006.5(4):p.453-79.
65.Chen,C.,Recent advances in small molecule antagonists of the corticotropin-releasing factor type-1 receptor-focus on pharmacology and pharmacokinetics.Curr Med Chem,2006.13(11):p.1261-82.
66.Tatemoto,K.,et al.,Galanin-a novel biologically active peptide from porcine intestine.FEBS Lett,1983.164(1):p.124-8.
67.Finn,P.D.,D.K.Clifton,and R.A.Steiner,The regulation of galanin gene expression in gonadotropin-releasing hormone neurons.Mol Cell Endocrinol,1998.140(1-2):p.137-42.
68.Crawley,J.N.,The role of galanin in feeding behavior.Neuropeptides,1999.33(5):p.369-75.
69.Miller,M.A.,Regulation of galanin in memory pathways.Ann N Y Acad Sci,1998.863:p.323-41.
70.Sauer-Ramirez,J.L.,L.M.Ballesteros,and O.Hernandez-Perez,[Galanin,a new neuropeptide.Review].Ginecol Obstet Mex,1996.64:p.325-31.
71.Leibowitz,S.F.,Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight.Ann N Y Acad Sci,1998.863:p.206-20.
72.Groneberg,D.A.,et al.,Neuropeptide Y(NPY).Pulm Pharmacol Ther,2004.17(4):p.173-80.
73.Tatemoto,K.,Neuropeptide Y:complete amino acid sequence of the brain peptide.Proc Natl Acad Sci U S A,1982.79(18):p.5485-9.
74.Allen,Y.S.,et al.,Neuropeptide Y distribution in the rat brain.Science,1983.221(4613):p.877-9.
75.Edvinsson,L.,et al.,Neuropeptide Y:cerebrovascular innervation and vasomotor effects in the cat.Neurosci Lett,1983.43(1):p.79-84.
76.Pesonen,U.,Human NPY gene variants in cardiovascular and metabolic diseases.EXS,2006(95):p.247-67.
77.Pelz,K.M.and J.Dark,ICV NPY Y1 receptor agonist but not Y5 agonist induces torpor-like hypothermia in cold-acclimated Siberian hamsters.Am J Physiol Regul Integr Comp Physiol,2007.292(6):p.R2299-311.
78.Chan,Y.Y.,D.K.Clifton,and R.A.Steiner,Role of NPY neurones in GH-dependent feedback signalling to the brain.Horm Res,1996.45 Suppl 1:p.12-4.
79.Sajdyk,T.J.,A.Shekhar,and D.R.Gehlert,Interactions between NPY and CRF in the amygdala to regulate emotionality.Neuropeptides,2004.38(4):p.225-34.
80.Tucker,G.J.,Neurological disorders and depression.Semin Clin Neuropsychiatry,2002.7(3):p.213-20.
81.Zhao,Z.,et al.,Hippocampus shape analysis and late-life depression.PLoS ONE,2008.3(3):p.e1837.
82.Sheline,Y.I.,B.L.Mittler,and M.A.Mintun,The hippocampus and depression.Eur Psychiatry,2002.17 Suppl 3:p.300-5.
83.Mervaala,E.,et al.,Quantitative MRI of the hippocampus and amygdala in severe depression.Psychol Med,2000.30(1):p.117-25.
84.Yi,P.L.,et al.,The involvement of metabotropic glutamate receptors in long-term depression of N-methyl-D-aspartate receptor-mediated synaptic potential in the rat hippocampus.Neurosci Lett,1995.185(3):p.207-10.
85.Walf,A.A.and C.A.Frye,A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior.Neuropsychopharmacology,2006.31(6):p.1097-111.
86.Davis,S.,S.P.Butcher,and R.G.Morris,The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate(D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro.J Neurosci,1992.12(1):p.21-34.
87.Katsube,T.,et al.,Changes of nutritional status after distal gastrectomy in patients with gastric cancer.Hepatogastroenterology,2008.55(86-87):p.1864-7.
88.Feng,Z.,et al.,Synthesis and activity in enhancing long-term potentiation(LTP) of clausenamide stereoisomers.Bioorg Med Chem Lett,2009.19(8):p.2112-5.
89.Dubrovsky,B.,A.Tatarinov-Levin,and J.Harris,Effects of the active neurosteroid allotetrahydrodeoxycorticosterone on long-term potentiation in the rat hippocampus:implications for depression.Prog Neuropsychopharmacol Biol Psychiatry,2004.28(6):p.1029-34.
90.Sasaki,T.,et al.,Reverse Optical Trawling for Synaptic Connections in Situ.J Neurophysiol,2009.
91.Youn,D.H.,et al.,Altered long-term synaptic plasticity and kainate-induced Ca2+transients in the substantia gelatinosa neurons in GLU(K6)-deficient mice.Brain Res Mol Brain Res,2005.142(1):p.9-18.
92.Thomas,L.,et al.,GENetic and clinical Predictors Of treatment response in Depression:the GenPod randomised trial protocol.Trials,2008.9:p.29.
93.Flint,J.,et al.,Genetic variants in major depression.Novartis Found Symp,2008.289:p.23-32;discussion 33-42,87-93.
94.Wasserman,D.,et al.,Depression in suicidal males:genetic risk variants in the CRHR1 gene.Genes Brain Behav,2009.8(1):p.72-9.
95.Power,A.C.and P.J.Cowen,Neuroendocrine challenge tests:assessment of 5-HT function in anxiety and depression.Mol Aspects Med,1992.13(3):p.205-20.
96.Sulser,F.,et al.,Regulation of recognition and action function of the norepinephrine(NE) receptor-coupled adenylate cyclase system in brain:implications for the therapy of depression.Neuropharmacology,1983.22(3 Spec No):p.425-31.
97.Yatham,L.N.,et al.,Hypothermic,ACTH,and Cortisol responses to ipsapirone in patients with mania and healthy controls.J Affect Disord,1999.54(3):p.295-301.
98.Whale,R,et al.,Decreased sensitivity of 5-HT(1D) receptors in melancholic depression.Br J Psychiatry,2001.178:p.454-7.
99.Pinchot,S.N.,R.Sippel,and H.Chen,ACTH-producing carcinoma of the pituitary with refractory Cushing's Disease and hepatic metastases:a case report and review of the literature.World J Surg Oncol,2009.7(1):p.39.
100.Ogren,S.O.,et al.,Alaproclate,a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia.J Neural Transm,1984.59(4):p.265-88.
101.Baicy,K.,et al.,Common substrates of dysphoria in stimulant drug abuse and primary depression:therapeutic targets.Int Rev Neurobiol,2005.65:p.117-45.
102.Janowsky,D.S.,et al.,A cholinomimetic model of motion sickness and space adaptation syndrome.Aviat Space Environ Med,1984.55(8):p.692-6.
103.Maj,M.,et al.,Agitated "unipolar" major depression:prevalence,phenomenology,and outcome.J Clin Psychiatry,2006.67(5):p.712-9.
104.Ossowska,K.,et al.,An influence of ligands of metabotropic glutamate receptor subtypes on parkinsonian-like symptoms and the striatopallidal pathway in rats.Amino Acids,2007.32(2):p.179-88.
105.Wrobel,A.,et al,Effect of chronic treatment with dexamethasone on brain dopamine receptors in mice.Pol J Pharmacol,2004.56(4):p.399-405.
106.Wardas,J.,et al.,The role of metabotropic glutamate receptors in regulation of striatal proenkephalin expression:implications for the therapy of Parkinson's disease.Neuroscience,2003.122(3):p.747-56.
107.Ossowska,K.,Neuronal basis of neuroleptic-induced extrapyramidal side effects.Pol J Pharmacol,2002.54(4):p.299-312.
108.Kleeberg,J.,et al.,ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase Cpathway in vivo.Am J Physiol Heart Circ Physiol,2004.286(4):p.H1339-46.
109.Swiecicki,L.,[Efficacy of citalopram in more than maximal dose in drug resistant depression.Case report].Psychiatr Pol,2003.37(5):p.839-44.
110.Pirkis,J.E.,Borderline personality disorder,drug use disorder,and worsening depression or substance abuse are significant predictors of suicide attempts in people with Axis Ⅰ and Ⅱdisorders.Evid Based Ment Health,2004.7(1):p.25.
111.Shelton,R.C.,et al.,Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A.Neuroscience,2009.158(4):p.1406-15.
112.Stein,M.D.,et al.,Pharmacotherapy plus psychotherapy for treatment of depression in active injection drug users.Arch Gen Psychiatry,2004.61(2):p.152-9.
113.Levy,S.E.,Microarray analysis in drug discovery:an uplifting view of depression.Sci STTCE,2003.2003(206):p.pe46.
114.Sandstrom,L.and E.E.Johansson,[Depression-a gender-disease in drug advertisement].Lakartidningen,2004.101(7):p.582-5.
115.Suljic,E.,et al.,[Comorbid depression in patients with epilepsy treated with single and multiple drug therapy].Med Arh,2003.57(5-6 Suppl 1):p.45-6.
116.Lambas-Senas,L.,et al.,Functional correlates for 5-HT(1A) receptors in maternally deprived rats displaying anxiety and depression-like behaviors.Prog Neuropsychopharmacol Biol Psychiatry,2009.33(2):p.262-8.
117.Vale,W.,et al.,Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.Science,1981.213(4514):p.1394-7.
118.Vella,E.J.and B.H.Friedman,Hostility and Anger In:Cardiovascular Reactivity and Recovery to Mental Arithmetic Stress.Int J Psychophysiol,2009.
119.Mitchell,A.J.,Depression as a risk factor for later dementia:a robust relationship? Age Ageing,2005.34(3):p.207-9.
120.Yalow,R.S.and S.A.Berson,Size heterogeneity of immunoreactive human ACTH in plasma and in extracts of pituitary glands and ACTH-producing thymoma.Biochem Biophys Res Commun,1971.44(2):p.439-45.
121.Marcus,S.M.,et al.,Gender differences in depression:findings from the STAR*D study.J Affect Disord,2005.87(2-3):p.141-50.
122.Young,A.M.and C.Boyd,Sexual Trauma,Substance Abuse,and Treatment Success in a Sample of African American Women Who Smoke Crack Cocaine.Subst Abus,2000.21(1):p.9-19.
123.Lundberg,J.M.,et al.,Neuropeptide Y(NPY)-like immunoreactfvity in peripheral noradrenergic neurons and effects of NPY on sympathetic function.Acta Physiol Scand,1982.116(4):p.477-80.
124.Allen,J.M.,et al.,Two novel related peptides,neuropeptide Y(NPY) and peptide YY(PYY)inhibit the contraction of the electrically stimulated mouse vas deferens.Neuropeptides,1982.3(2):p.71-7.
125.Chesher,T.and M.Young,Developing innovative strategies for multicultural communication.N S W Public Health Bull,2000.11(11):p.178-180.
126.Caberlotto,L.,et al.,Corticotropin-releasing hormone(CRH) mRNA expression in rat central amygdala in cannabinoid tolerance and withdrawal:evidence for an allostatic shift?Neuropsychopharmacology,2004.29(1):p.15-22.
127.Sandi,C.,et al.,Chronic stress-induced alterations in amygdala responsiveness and behavior-modulation by trait anxiety and corticotropin-releasing factor systems.Eur J Neurosci,2008.28(9):p.1836-48.
128.Shen,P.J.,J.A.Larm,and A.L.Gundlach,Expression and plasticity of galanin systems in cortical neurons,oligodendrocyte progenitors and proliferative zones in normal brain and after spreading depression.Eur J Neurosci,2003.18(6):p.1362-76.
129.Kuteeva,E.,et al.,Galanin,galanin receptor subtypes and depression-like behaviour.Cell Mol Life Sci,2008.65(12):p.1854-63.
130.Kask,K.,M.Berthold,and T.Bartfai,Galanin receptors:involvement in feeding,pain,depression and Alzheimer's disease.Life Sci,1997.60(18):p.1523-33.
131.Kuteeva,E.,et al.,Differential role of galanin receptors in the regulation of depression-like behavior and mono amine/stress-related genes at the cell body level.Neuropsychopharmacology,2008.33(11):p.2573-85.
132.Holmes,A.,et al.,Phenotypic assessment ofgalanin over expressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior.Psychopharmacology(Berl),2005.178(2-3):p.276-85.
133.Chinet,L.,et al.,Substance use and depression.Comparative course in adolescents.Eur Child Adolesc Psychiatry,2006.15(3):p.149-55.
134.Evren,C.,S.Kural,and M.Erkiran,Antisocial personality disorder in Turkish substance dependent patients and its relationship with anxiety,depression and a history of childhood abuse.Isr J Psychiatry Relat Sci,2006.43(1):p.40-6.
135.Rotheram-Borus,M.J.,et al.,Substance use and its relationship to depression,anxiety,and isolation among youth living with HIV.Int J Behav Med,1999.6(4):p.293-311.