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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization
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Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

机译:安非他明致敏需要多巴胺D1受体(D1R)和D2R表达的中棘神经元中平衡的NMDA受体活性

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摘要

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1R MSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.
机译:通过N-甲基-D-天冬氨酸型谷氨酸受体(NMDARs)发出的信号对于对精神兴奋剂如苯丙胺(AMPH)的行为敏感发展至关重要。但是,仍需要解决NMPH致敏需要NMDAR信号的细胞类型和大脑区域。在这里,我们使用多巴胺神经元或它们的中棘神经元(MSN)目标中编码NMDARs的基本NR1亚基的Grin1的选择性失活来解决这个问题。我们表明,多巴胺神经元中的NMDAR信号对于AMPH的行为敏化不是必需的。相反,从表达多巴胺D1受体(D1R)的MSN中去除NMDAR可以显着减弱AMPH致敏作用,并且这些动物伏隔核(NAc)的D1R神经元中有条件的,病毒介导的NR1的有条件恢复可以拯救致敏作用。有趣的是,也可以通过在D1R神经元上缺少NMDAR的动物的NAc中所有剩余的神经元中病毒介导的NR1失活或从所有MSN中去除NMDAR来恢复敏化作用。综上所述,这些数据表明,仅在D1R MSN中不平衡丢失NMDAR信号就可以防止AMPH致敏,而从D1R和多巴胺D2受体表达(D2R)MSN中都可以使NMDAR平衡丢失对敏化是允许的。

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    Department of Genome Sciences, University of Washington, Seattle, WA 98195;

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195;

    Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Department of Biochemistry, University of Washington, Seattle, WA 98195;

    Department of Pharmacology, University of Washington, Seattle, WA 98195;

    Departments of Neurology, Pediatrics, and Psychology, and Center on Human Development and Disability, University of Washington,Seattle Children's Hospital, Seattle, WA 98105;

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195 Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Department of Pharmacology, University of Washington, Seattle, WA 98195;

    Department of Genome Sciences, University of Washington, Seattle, WA 98195 Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Department of Biochemistry, University of Washington, Seattle, WA 98195;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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