大鼠海马NPY、5-HT、PAM与慢性不可预见性应激抑郁症的关系
摘要
抑郁症(depression)是一种以情感病态变化主要是情绪低落为显著特征的精神疾病,它的发病与逐渐增大的各种压力带来的应激性事件有关。应激(stress)是生物在生存过程中受到各种各样的刺激后产生的非特异性适应性反应,一定频率和强度的应激会导致生物个体产生情绪和认知等方面的障碍,诱发抑郁症。应激引起抑郁的机制涉及多个脑区的多种神经递质,大量的研究表明海马(hippocampus)这一应激激素作用的靶部位,是抑郁症研究中涉及最多的脑区,研究表明海马5-HT、NPY单独对抑郁症有调节作用,但是人们并不清楚海马的5-HT、NPY系统如何联合对慢性不可预见性应激(Chronic unpredicted mild stress CUMS)引起的抑郁症起作用;同时PAM是依赖于Cu~(2+)、维生素C、O_2的神经肽加工酶,它可以使NPY羧基末端的甘氨酸残基酰胺化。研究表明,PAM基因半敲除的小鼠表现出焦虑的行为,NPY在癫痫易感性中发挥关键性的作用,当诱导癫痫发生的药pentylenetetrazole(PTZ)被注射给小鼠时,只有PAM基因半敲除的小鼠的NPY表达显著升高,因此PAM可能是通过酰胺化的NPY起抗焦虑和癲痫的作用,但CUMS引起的抑郁是否与PAM表达变化相关,目前还没有报道。本实验旨在探讨CUMS对大鼠行为学表现的影响及其与海马NPY、5-HT、peptidylglycine-amidatingmonooxygenase(PAM)的关系。因此我们采用慢性不可预见性应激建立抑郁模型,通过海马微量注射5-HT、NPY及其相应受体阻断剂,利用体重变化率、糖水偏爱实验、敞箱实验、强迫游泳实验等方法观察大鼠行为学表现,同时利用免疫组织化学方法测定大鼠海马CA3区和齿状回(dental gyrus DG)5-HT、NPY、PAM表达的变化。结果行为学结果显示①对照组大鼠的体重在第7天、第14天、第21天持续增加,而CUMS组大鼠的体重持续降低;同时,CUMS组大鼠的糖水消耗率、水平运动、垂直运动、自我修饰的次数也显著降低(p<0.01),游泳不动时间显著延长(p<0.01):②NPY、5-HT使CUMS大鼠的体重在第7天、第14天、第21天持续增加,且NPY的作用比5-HT的作用强,在第14天和第21天,注射NPY的大鼠其体重和对照组大鼠的体重无显著性差异。CUMS并注射NPY和5-HT组大鼠的糖水消耗率、水平运动、垂直运动、自我修饰的次数与CUMS组大鼠相比显著升高(p<0.01),游泳不动时间与CUMS组相比显著降低(p<0.01):③单胺类受体阻断剂Spiperone在前两周不影响NPY增加大鼠体重的作用,但在第3周显著抑制NPY增加大鼠体重的作用:NPYY1受体阻断剂GR231118对5-HT有相同的作用。单胺类受体阻断剂利NPYY1受体阻断剂分别对NPY和5-HT引起的糖水消耗率的增加没有显著的抑制作用(p>0.05),然而,这两个阻断剂分别抑制NPY和5-HT引起的水平运动、垂直运动、自我修饰的次数的增加,而且它们也能降低大鼠的游泳不动时间(p<0.01/0.05)。免疫组织化学结果显示:①CUMS组大鼠在应激结束后,海马齿状回5-HT、NPY、PAM阳性表达均显著下降,与对照组相比差异极其显著(P<0.01)。②PY+CUMS组大鼠在应激结束后,海马DG区5-HT、PAM阳性表达均显著提高,与CUMS组比较差异极其显著(P<0.01)。③5-HT+CUMS组大鼠在应激结束后,海马齿状回NPY、PAM阳性表达显著提高,与CUMS组相比差异极其显著(P<0.01)。④Spiperone+NPY+CUMS组大鼠在应激结束后,海马DG区5-HT、PAM阳性表达均显著下降,与对照组相比差异极其显著(P<0.01)。⑤GR231118+5-HT+CUMS组大鼠在应激结束后,海马DG区NPY、PAM阳性表达均显著下降,与对照组相比差异极其显著(P<0.01)。结论CUMS能够引起大鼠抑郁,其特征是动物快感缺失,兴趣丧失,体重降低,生理活动迟缓及行为绝望。CUMS引起海马齿状回5-HT、NPY、PAM下降是抑郁产生的原因之一,重复的在单侧背部海马注射NPY和5-HT能够抑制或阻断CUMS引起的抑郁症状,而且NPY一方面通过提高5-HT的表达起抗抑郁作用,另一方面是增加PAM,引起NPY酰胺化,从而起到抗抑郁作用。5-HT既能增加海马NPY又能增加PAM,促进NPY酰胺化。单胺类受体阻断剂Spiperone可以抑制或阻断NPY对CUMS引起的抑郁症的治疗作用及NPY提高5-HT、PAM的表达:同时,NPY Y1受体阻断剂GR231118也能影响5-HT的作用。说明NPY可以通过单胺类受体起抗抑郁作用,而且此抗抑郁作用的发挥通过5-HT、PAM的表达完成;5-HT可以使NPY、PAM的表达增强,通过NPY Y1受体起到抗抑郁作用。因此,海马中NPY和5-HT这两种神经递质参与了抗CUMS引起抑郁,且5-HT和NPY系统的相互作用是一个重要途径。而PAM表达降低可能是抑郁症发生的重要原因之一。
Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) neuropeptide Y (NPY) in the response to stress and modulation of depression. Peptidylglycineα-amidating monooxygenase (PAM) is a rate-limiting enzyme essential for the production of multiple bioactive neuropeptides, including NPY. But it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression, an animal model of depression that closely mimics human depression. It is also unclear whether PAM has the relationship with CUMS induced depression. Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of behavioral measures of depression, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test , and a significant increase in immobility time in forced swimming test. So, our current protocol of a 3-week CUMS is able to induce a reliable rat model of depression with anhedonia, loss of interests, lost weight, psychomotor retardation and behavioral despair. We also observed the expression of NPY, 5-HT and PAM- immunopositive neurons in the dental gyrus (DG) of hippocampus in these groups ,which indicates that the depression induced by CUMS maybe is related with the decreased expression of hippocampal NPYor5-HT or maybe is related with the reduced amidated NPY induced by reduced PAM. While repeated injections of 5-HT or NPY into one side of the dorsal hippocampus can suppress or block CUMS-induced anhedonia, loss of interests, psychomotor retardation and behavioral despair. The beneficial effects of NPY and 5-HT on behavioral measures of depression were suppressed by pretreatment with the monoamine receptor antagonist Spiperone and the NPY Y1 receptor antagonist GR231118, respectively. These data suggest, reduced 5-HT and NPY neurotransmission in the hippocampus may make significant contributions to CUMS-induced depression via the interaction of hippocampal 5-HT and NPY systems. The decreased expression of PAM maybe is a main reason for depression.
Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) neuropeptide Y (NPY) in the response to stress and modulation of depression. Peptidylglycineα-amidating monooxygenase (PAM) is a rate-limiting enzyme essential for the production of multiple bioactive neuropeptides, including NPY. But it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression, an animal model of depression that closely mimics human depression. It is also unclear whether PAM has the relationship with CUMS induced depression. Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of behavioral measures of depression, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test , and a significant increase in immobility time in forced swimming test. So, our current protocol of a 3-week CUMS is able to induce a reliable rat model of depression with anhedonia, loss of interests, lost weight, psychomotor retardation and behavioral despair. We also observed the expression of NPY, 5-HT and PAM- immunopositive neurons in the dental gyrus (DG) of hippocampus in these groups ,which indicates that the depression induced by CUMS maybe is related with the decreased expression of hippocampal NPYor5-HT or maybe is related with the reduced amidated NPY induced by reduced PAM. While repeated injections of 5-HT or NPY into one side of the dorsal hippocampus can suppress or block CUMS-induced anhedonia, loss of interests, psychomotor retardation and behavioral despair. The beneficial effects of NPY and 5-HT on behavioral measures of depression were suppressed by pretreatment with the monoamine receptor antagonist Spiperone and the NPY Y1 receptor antagonist GR231118, respectively. These data suggest, reduced 5-HT and NPY neurotransmission in the hippocampus may make significant contributions to CUMS-induced depression via the interaction of hippocampal 5-HT and NPY systems. The decreased expression of PAM maybe is a main reason for depression.
引文
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