Kippin Tod E, Kapur Shitij, van der Kooy Derek
Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
J Neurosci. 2005 Jun 15;25(24):5815-23. doi: 10.1523/JNEUROSCI.1120-05.2005.
Neurogenesis has been implicated in antidepressant drug action and animal models of depression, suggesting that proliferating cells play a role in psychiatric disorders. Similar studies using antipsychotic drugs have yielded conflicting results, perhaps because of the lack of focus on specific cell types. We examine the effect of haloperidol on neural stem cells (NSCs), the ultimate precursors for adult cell genesis. We show that haloperidol increases NSC numbers, resulting in more progenitors and more new neurons and glia in the adult rat brain. The increase in NSCs by haloperidol is dependent on central dopamine D2 receptors, and these receptors are expressed by NSCs. D2 receptor stimulation in vitro inhibits NSC proliferation, which is reversed by haloperidol. Thus, haloperidol increases adult mammalian brain proliferation by antagonizing dopamine at D2 receptors on NSCs. These findings demonstrate a direct link between neural activity and NSC proliferation and implicate cell genesis in antipsychotic drug effects.
神经发生与抗抑郁药物作用及抑郁症动物模型有关，这表明增殖细胞在精神疾病中发挥作用。使用抗精神病药物的类似研究得出了相互矛盾的结果，这可能是因为缺乏对特定细胞类型的关注。我们研究了氟哌啶醇对神经干细胞（NSCs）的影响，神经干细胞是成体细胞生成的最终前体细胞。我们发现氟哌啶醇增加了神经干细胞的数量，导致成年大鼠大脑中产生更多的祖细胞以及更多的新神经元和神经胶质细胞。氟哌啶醇引起的神经干细胞增加依赖于中枢多巴胺D2受体，并且这些受体由神经干细胞表达。体外D2受体刺激会抑制神经干细胞增殖，而氟哌啶醇可逆转这种抑制作用。因此，氟哌啶醇通过拮抗神经干细胞上D2受体的多巴胺来增加成年哺乳动物大脑的细胞增殖。这些发现证明了神经活动与神经干细胞增殖之间的直接联系，并表明细胞生成与抗精神病药物的作用有关。
