Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice.
Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice.
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DOI：
10.1523/jneurosci.4287-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
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通讯作者：
Alvarez VA
中科院分区：
文献类型：
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作者：
Kramer PF;Christensen CH;Hazelwood LA;Dobi A;Bock R;Sibley DR;Mateo Y;Alvarez VA
BAC转基因小鼠在D1和D2多巴胺受体启动子的控制下表达荧光报告蛋白EGFP（Drd 1-EGFP和Drd 2-EGFP），已被广泛用于研究纹状体功能，并有助于我们理解基底神经节的生理和病理功能。这些工具被生产出来，并迅速提供给人们，以细胞特异性的方式解决问题，这改变了我们在神经科学中构建假设的方式。然而，这些小鼠到目前为止还没有得到充分的表征。我们发现，与野生型和Drd 1-EGFP小鼠相比，Drd 2-EGFP小鼠显示多巴胺D2受体（D2 R）的膜表达增加约40%，纹状体中D2 R mRNA水平增加两倍。D2 R过表达伴随着对D2 R样激动剂的行为超敏反应，以及中脑多巴胺能神经元对D2 R激活的电生理反应增强。多巴胺瞬变引起的刺激在核延髓显示较慢的清除在Drd 2-EGFP小鼠和可卡因的DA清除行动受损，在这些小鼠。因此，发现Drd 2-EGFP小鼠在暴露于新环境时过度活跃并且运动被急性可卡因施用抑制并不令人惊讶。总而言之，这项研究表明Drd 2-EGFP小鼠过度表达D2 R，并且改变了多巴胺能信号传导，这从根本上将它们与野生型和Drd 1-EGFP小鼠区分开来。
BAC transgenic mice expressing the fluorescent reporter protein EGFP under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological function of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display a ~40% increase in membrane expression of the dopamine D2 receptor (D2R) and a two-fold increase in D2R mRNA levels in the striatum when compared to wild-type and Drd1-EGFP mice D2R over-expression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. DA transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice over-express D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice.