Psychotropic drug-induced locomotor hyperactivity and prepulse inhibition regulation in male and female aromatase knockout (ArKO) mice: role of dopamine D1 and D2 receptors and dopamine transporters
Psychotropic drug-induced locomotor hyperactivity and prepulse inhibition regulation in male and female aromatase knockout (ArKO) mice: role of dopamine D1 and D2 receptors and dopamine transporters
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DOI：
10.1007/s00213-009-1604-6
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发表时间：
2009-10-01
影响因子：
3.4
通讯作者：
van den Buuse, Maarten
中科院分区：
文献类型：
--
作者：
Chavez, Carolina;Gogos, Andrea;van den Buuse, Maarten
本研究的目的是探讨雌激素在精神分裂症中的可能作用，通过比较芳香酶敲除（ArKO）小鼠，这是不能产生雌激素，与野生型对照使用两种行为动物模型与疾病，精神药物诱导的运动过度活跃和前脉冲抑制（PPI）。基线PPI ArKO和对照之间没有差异。阿扑吗啡，MK-801和安非他明治疗引起PPI在所有组中的中断。然而，在雌性而非雄性ArKO小鼠中，阿扑吗啡和苯丙胺的作用均降低。在雌性ArKO小鼠中，安非他明诱导的过度运动明显减少，但在雄性小鼠中，基因型差异要小得多。雌性而非雄性ArKO小鼠也显示苯环己哌啶诱导的运动过度活跃减少。与野生型小鼠相比，雄性而非雌性ArKO小鼠的尾壳核中多巴胺转运蛋白的密度显著增加，但D-1和D-2受体的密度没有显著增加。这可能代表雄性ArKO小鼠中的补偿性多巴胺能上调。由于它们缺乏雌激素产生，预计ArKO小鼠将显示安非他明对运动活性和PPI的增强作用。相反，在这些动物中，芳香酶敲除似乎是“保护性的”。这可能代表了在组成型敲除模型（如ArKO小鼠）中模拟复杂疾病（如精神分裂症）的能力的局限性。此外，目前的结果可能指向其他性类固醇的参与，这也改变了ArKO小鼠，多巴胺能控制的行为。
The aim of the present study was to investigate the possible role of oestrogen in schizophrenia by comparing aromatase knockout (ArKO) mice, which are unable to produce oestrogen, with wild-type controls using two behavioural animal models with relevance to the illness, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI).Baseline PPI was not different between ArKO and controls. Treatment with apomorphine, MK-801 and amphetamine caused disruption of PPI in all groups. However, in female but not male ArKO mice, the effect of both apomorphine and amphetamine was reduced. In female ArKO mice, amphetamine-induced hyperlocomotion was markedly reduced, but in male mice, the genotype difference was far smaller. Female but not male ArKO mice also showed a reduction of phencyclidine-induced locomotor hyperactivity. The density of dopamine transporters, but not D-1 and D-2 receptors, was significantly increased in the caudate putamen of male but not female ArKO mice compared to wild-type mice. This could represent a compensatory dopaminergic upregulation in male ArKO mice.Because of their lack of oestrogen production, it was anticipated that ArKO mice would display enhanced effects of amphetamine on locomotor activity and PPI. Instead, in these animals, aromatase knockout appeared to be 'protective'. This may represent limitations in the ability to model a complex illness such as schizophrenia in a constitutive knockout model, such as ArKO mice. Moreover, the current results may point at the involvement of other sex steroids, which are also altered in ArKO mice, in dopaminergic control of behaviour.