Critical role of the embryonic mid-hindbrain organizer in the behavioral response to amphetamine and methylphenidate.
Critical role of the embryonic mid-hindbrain organizer in the behavioral response to amphetamine and methylphenidate.
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DOI：
10.1016/j.neuroscience.2009.07.040
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发表时间：
2009-11-10
期刊：
影响因子：
3.3
通讯作者：
Brodski, C.
中科院分区：
文献类型：
--
作者：
Tilleman, H.;Kofman, O.;Nashelsky, L.;Livneh, U.;Roz, N.;Sillaber, I.;Biegon, A.;Rehavi, M.;Brodski, C.
胚胎中后脑组织者是由脑干中的瞬时细胞群组成的，它控制着多巴胺能和血清素能神经元的发育。决定这种胚胎结构的位置和活性的不同基因与多巴胺和血清素相关疾病有关。具有尾部移动的中后脑组织者的小鼠突变体过度活跃，显示出多巴胺能神经元数量增加和血清素能细胞数量减少。在目前的研究中，我们使用这些突变体来深入了解运动活动和对精神兴奋剂的反应的遗传和发育机制。为此，我们研究了这些动物在暴露于哌甲酯和安非他明后的运动活动，并表征了它们的多巴胺能和血清素能神经支配。与野生型小鼠相比，经盐水处理的突变体表现出更强的运动能力、更多的刻板行为和更少的饲养时间。这一基线活动水平与在高剂量精神兴奋剂治疗的野生型动物中观察到的行为相似。在突变体中，与野生型小鼠相比，哌甲酯（5或30 mg/kg）或安非他明（2或4 mg/kg）没有进一步增加活动，甚至导致运动活动减少。氟西汀（5毫克或10毫克/公斤）将突变体的过度活跃程度降低到野生型的水平。递质测量、多巴胺和5 -羟色胺转运体结合测定和放射自显影显示，突变体纹状体多巴胺能神经支配略有增加，5 -羟色胺能神经支配明显减少。综上所述，我们的数据表明，中后脑组织者位置异常的小鼠对精神兴奋剂的敏感性发生了改变，血清素能神经传递的增加逆转了它们的多动症。我们的结论是，通过协调多巴胺能神经元和血清素能神经元的形成，中脑组织者是运动活动和精神兴奋剂反应的重要发育参数。
The embryonic mid-hindbrain organizer, which is composed of a transient cell population in the brainstem, controls the development of dopaminergic and serotonergic neurons. Different genes determining the position and activity of this embryonic structure have been implicated in dopamine and serotonin associated disorders. Mouse mutants with a caudally shifted mid-hindbrain organizer, are hyperactive, show increased numbers of dopaminergic neurons and a reduction in serotonergic cells. In the present study we used these mutants to gain insights into the genetic and developmental mechanisms underlying motor activity and the response to psychostimulants. To this end we studied the motor activity of these animals after exposure to methylphenidate and amphetamine and characterized their dopaminergic and serotonergic innervation. Saline-treated mutants showed increased locomotion, more stereotypic behaviour and a decrease in rearing compared to wild-type mice. This baseline level of activity was similar to behaviours observed in wild-type animals treated with high doses of psychostimulants. In mutants methylphenidate (5 or 30 mg/kg) or amphetamine (2 or 4 mg/kg) did not further increase activity or even caused a decrease of locomotor activity, in contrast to wild-type mice. Fluoxetine (5 mg or 10 mg/kg) reduced hyperactivity of mutants to levels observed in wild-types. Transmitter measurements, dopamine and serotonin transporter binding assays and autoradiography, indicate a subtle increase in striatal dopaminergic innervation and a marked general decrease of serotonergic innervation in mutants. Taken together, our data suggest that mice with an aberrantly positioned mid-hindbrain organizer show altered sensitivity to psychostimulants and that an increase of serotonergic neurotransmission reverses their hyperactivity. We conclude that the mid-hindbrain organizer, by orchestrating the formation of dopaminergic and serotonergic neurons, is an essential developmental parameter of locomotor activity and psychostimulant response.
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影响因子：
30.8
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Emamian, ES;Hall, D;Gogos, JA
通讯作者：
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