Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates.
Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates.
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DOI：
10.1371/journal.pone.0017600
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发表时间：
2011-04-15
期刊：
影响因子：
3.7
通讯作者：
Coplan JD
中科院分区：
文献类型：
--
作者：
Perera TD;Dwork AJ;Keegan KA;Thirumangalakudi L;Lipira CM;Joyce N;Lange C;Higley JD;Rosoklija G;Hen R;Sackeim HA;Coplan JD
啮齿动物研究表明，神经发生对于调节抗抑郁药物的有益作用是必要的。非人灵长类动物(NHP)的研究可能会将重要的啮齿动物研究结果连接到临床领域，因为NHP-抑郁症与人类抑郁症具有显著的同源性，并且灵长类动物的神经发生动力学不同于啮齿动物。在证明抗抑郁药物可以刺激NHP中的神经再生之后，我们目前的研究检验了NHP中抗抑郁药物的疗效是否需要神经再生。成年女帽被随机分成三个社交圈(N = ，每个圈6个)。PEN-1受试者暴露在对照条件下15周，其中一半接受抗抑郁药物氟西汀，其余接受生理盐水安慰剂。PEN-2受试者接受了15周的分离应激，其中一半接受氟西汀治疗，另一半接受安慰剂治疗。PEN-3受试者接受2周的照射(N = 4)或假照射(N = 2)，然后暴露于15周的应激和氟西汀。依赖的测量是每周的行为观察和死后神经发生水平。将NHP暴露在重复的分离应激下会导致抑郁样行为(快感缺失和从属)，并伴随着海马神经发生的减少。使用氟西汀治疗可刺激神经发生，并防止抑郁样行为的出现。放射线消融神经发生后，氟西汀的治疗作用消失。尽管接受氟西汀治疗的对照组有更高的神经生发率，但非应激对照组有正常的行为。在所有组中，抑郁样行为与神经新生率降低有关，但这种负相关只对处于完全成熟门槛的前齿状回中的新神经元显著。我们提供的证据表明，诱导神经发生是氟西汀治疗NHP疗效所不可或缺的。鉴于猴子和人类之间的相似性，海马神经发生在临床抑郁症的治疗中可能扮演着类似的角色。未来的研究将检验几个悬而未决的问题，例如神经抑制是否足以产生抑郁，以及氟西汀的治疗神经整形作用是否针对抗抑郁药物。
Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels. Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation. We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.
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DOI：
10.1073/pnas.96.10.5768
发表时间：
1999-05-11
影响因子：
11.1
作者：
Kornack, DR;Rakic, P
通讯作者：
Rakic, P
DOI：
10.1073/pnas.120552597
发表时间：
2000-06-20
影响因子：
11.1
作者：
Eisch, AJ;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1073/pnas.93.4.1619
发表时间：
1996-02-20
影响因子：
11.1
作者：
Coplan, JD;Andrews, MW;Nemeroff, CB
通讯作者：
Nemeroff, CB
影响因子：
2.5
作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
通讯作者：
Kuhn, HG
影响因子：
3.4
作者：
Couillard-Despres, S;Winner, B;Aigner, L
通讯作者：
Aigner, L